Phenoxymethyl derivatives

ABSTRACT

The invention provides novel compounds having the general formula (I) 
                         
wherein R A , R B , R C , R C1  and W are as defined herein, compositions including the compounds and methods of using the compounds.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of Ser. No. 15/910,307, filed Mar. 2,2018, now U.S. Pat. No. 10,640,472, which is a continuation ofInternational Application No. PCT/EP2016/070561, filed Sep. 1, 2016,which claims benefit of priority to EP Application No. 15197364.1, filedDec. 1, 2015 and EP Application No. 15183953.7, filed Sep. 4, 2015, eachof which is incorporated herein by reference in its entirety.

The present invention relates to organic compounds useful for therapy orprophylaxis in a mammal, and in particular to autotaxin (ATX) inhibitorswhich are inhibitors of lysophosphatidic acid (LPA) production and thusmodulators of LPA levels and associated signaling, for the treatment orprophylaxis of renal conditions, liver conditions, inflammatoryconditions, conditions of the nervous system, conditions of therespiratory system, vascular and cardiovascular conditions, fibroticdiseases, cancer, ocular conditions, metabolic conditions, cholestaticand other forms of chronic pruritus and acute and chronic organtransplant rejection.

The present invention provides novel compounds of formula (I)

-   -   wherein    -   R_(A) is selected from the group consisting of        -   i) C₁-C₆-alkyl,        -   ii) cyano-C₁-C₆-alkyl,        -   iii) C₃-C₈-cycloalkyl,        -   iv) halo-C₁-C₆-alkoxy,        -   v) halo-C₁-C₆-alkyl,        -   vi) aryl substituted with R_(G), R_(G1) and R_(G2),        -   vii) heterocycloalkyl substituted with R_(G), R_(G1) and            R_(G2), and        -   viii) heteroaryl substituted with R_(G), R_(G1) and R_(G2):    -   R_(B) is selected from the group consisting of        -   i) C₁-C₆-alkyl,        -   ii) C₃-C₈-cycloalkyl,        -   iii) C₁-C₆-alkylsulfonyl,        -   iv) C₃-C₈-cycloalkylsulfonyl,        -   v) C₁-C₆-alkylsulfonylamino,        -   vi) C₃-C₈-cycloalkylsulfonylamino,        -   vii) aminocarbonyl,        -   viii) cyano,        -   ix) halogen,        -   x) halo-C₁-C₆-alkoxy,        -   xi) halo-C₁-C₆-alkyl,        -   xii) heterocycloalkyl, and        -   xiii) heteroaryl substituted with one H, C₁-C₆-alkyl or            trialkylsilyl-C₁-C₆-alkoxy-C₁-C₆-alkyl;    -   R_(C) and R_(C1) are independently selected from the group        consisting of        -   i) H,        -   ii) C₁-C₆-alkyl,        -   iii) C₃-C₈-cycloalkyl,        -   iv) halo-C₁-C₆-alkoxy,        -   v) halo-C₁-C₆-alkyl, and        -   vi) halogen;    -   or R_(B) and R_(C) together with the carbon atoms to which they        are attached form a ring system selected from the group        consisting of        -   i) C₃-C₈-cycloalkyl substituted with one to two substituent            independently selected from H, C₁-C₆-alkyl,            halo-C₁-C₆-alkoxy, halo-C₁-C₆-alkyl and C₃-C₈-cycloalkyl,        -   ii) heterocycloalkyl substituted with one to two substituent            independently selected from H, C₁-C₆-alkyl,            halo-C₁-C₆-alkoxy, halo-C₁-C₆-alkyl and C₃-C₈-cycloalkyl,        -   iii) aryl substituted with one to two substituent            independently selected from H, halogen, C₁-C₆-alkyl,            halo-C₁-C₆-alkoxy, halo-C₁-C₆-alkyl and C₃-C₈-cycloalkyl,            and        -   iv) heteroaryl substituted with one to two substituent            independently selected from H, halogen, C₁-C₆-alkyl,            halo-C₁-C₆-alkoxy, halo-C₁-C₆-alkyl and C₃-C₈-cycloalkyl:    -   W is selected from the ring systems A, B, C, D, E, F and G;

-   -   A¹, A³ and A⁴ are —CH— and A² is —CR_(D2)—,    -   A¹ is —N—, A² is —CR_(D2)—, A³ is —CH— or —N— and A⁴ is —CH—,    -   A¹, A³ and A⁴ are —CH— and A² is —N—,    -   A¹, A² and A⁴ are —CH— and A³ is —N—, or    -   A¹ and A³ are —CH—, A² is —CR_(D2)— and A⁴ is —N—;    -   one of A⁵ and A⁶ is —NR_(D3)— and the other one is        —CR_(L)R_(M)—;    -   R_(D1) is selected from the group consisting of        -   i) H,        -   ii) C₁-C₆-alkyl,        -   iii) halo-C₁-C₆-alkoxy,        -   iv) halo-C₁-C₆-alkyl, and        -   v) C₃-C₈-cycloalkyl;    -   R_(D2) is selected from the group consisting of        -   i) H,        -   ii) halogen,        -   iii) C₁-C₆-alkoxy-C₁-C₆-alkylcarbonyl,        -   iv) C₁-C₆-alkoxycarbonyl,        -   v) C₁-C₆-alkylcarbonyl,        -   vi) C₃-C₈-cycloalkylcarbonyl,        -   vii) C₁-C₆-alkyl,        -   viii) C₃-C₈-cycloalkyl,        -   ix) hydroxy-C₁-C₆-alkoxy,        -   x) hydroxy-C₁-C₆-alkyl(C₁-C₆-alkyl)amino,        -   xi) hydroxy-C₁-C₆-alkylamino,        -   xii) hydroxy-C₁-C₆-alkyl,        -   xiii) dihydroxy-C₁-C₆-alkoxy,        -   xiv) dihydroxy-C₁-C₆-alkyl(C₁-C₆-alkyl)amino,        -   xv) dihydroxy-C₁-C₆-alkylamino,        -   xvi) dihydroxy-C₁-C₆-alkyl,        -   xvii) halo-C₁-C₆-alkoxy,        -   xviii) halo-C₁-C₆-alkyl,        -   xix) heterocycloalkyl,        -   xx) heterocycloalkylcarbonyl, and        -   xxi) aminocarbonyl substituted on the nitrogen atom with one            to two independently selected C₁-C₆-alkyl;    -   R_(D3) is selected from the group consisting of        -   i) H,        -   ii) C₁-C₆-alkoxy-C₁-C₆-alkylcarbonyl,        -   iii) C₁-C₆-alkoxycarbonyl,        -   iv) C₁-C₆-alkylcarbonyl,        -   v) C₃-C₈-cycloalkylcarbonyl,        -   vi) C₁-C₆-alkyl,        -   vii) C₃-C₈-cycloalkyl,        -   viii) halo-C₁-C₆-alkoxy,        -   ix) halo-C₁-C₆-alkyl,        -   x) hydroxy-C₁-C₆-alkyl, and        -   xi) dihydroxy-C₁-C₆-alkyl,    -   R_(D4) is selected from the group consisting of        -   i) H,        -   ii) C₁-C₆-alkoxy-C₁-C₆-alkylcarbonyl,        -   iii) C₁-C₆-alkoxycarbonyl,        -   iv) C₁-C₆-alkylcarbonyl,        -   v) C₃-C₈-cycloalkylcarbonyl,        -   vi) C₁-C₆-alkyl,        -   vii) C₃-C₈-cycloalkyl,        -   viii) halo-C₁-C₆-alkoxy,        -   ix) halo-C₁-C₆-alkyl,        -   x) heterocycloalkylcarbonyl,        -   xi) aminocarbonyl substituted on the nitrogen atom with one            to two independently selected C₁-C₆-alkyl, and        -   xii) aryl substituted with one to three substituents            independently selected from H, C₁-C₆-alkyl,            C₃-C₈-cycloalkyl, halo-C₁-C₆-alkyl and halo-C₁-C₆-alkoxy;    -   R_(D5), R_(D6) and R_(D7) are independently selected from the        group consisting of        -   i) H,        -   ii) C₁-C₆-alkyl,        -   iii) C₁-C₆-alkoxy        -   iv) halo-C₁-C₆-alkoxy,        -   v) halo-C₁-C₆-alkyl,        -   vi) C₃-C₈-cycloalkyl, and        -   vii) C₃-C₈-cycloalkoxy;    -   R_(D8) is selected from the group consisting of        -   i) H,        -   ii) C₁-C₆-alkyl,        -   iii) C₁-C₆-alkoxy        -   iv) halo-C₁-C₆-alkoxy,        -   v) halo-C₁-C₆-alkyl,        -   vi) C₃-C₈-cycloalkyl,        -   vii) C₁-C₆-alkoxy-C₁-C₆-alkylcarbonyl,        -   viii) C₁-C₆-alkoxycarbonyl,        -   ix) C₁-C₆-alkylcarbonyl,        -   x) C₃-C₈-cycloalkylcarbonyl,        -   xi) heterocycloalkylcarbonyl, and        -   xii) aminocarbonyl substituted on the nitrogen atom with one            to two independently selected C₁-C₆-alkyl;    -   R_(G) is selected from the group consisting of        -   i) H,        -   ii) C₁-C₆-alkoxy,        -   iii) C₁-C₆-alkoxy-C₁-C₆-alkylcarbonylamino-C₁-C₆-alkyl,        -   iv)            C₁-C₆-alkoxy-C₁-C₆-alkylcarbonyl(C₁-C₆-alkyl)amino-C₁-C₆-alkyl,        -   v) C₁-C₆-alkoxycarbonyl,        -   vi) C₁-C₆-alkyl,        -   vii) C₁-C₆-alkylsulfonyl,        -   viii) C₃-C₈-cyloalkylsulfonyl,        -   ix) carboxy,        -   x) cyano,        -   xi) C₃-C₈-cycloalkyl,        -   xii) C₃-C₈-cycloalkoxy,        -   xiii) C₃-C₈-cycloalkylcarbonylamino-C₁-C₆-alkyl,        -   xiv) C₃-C₈-cycloalkylcarbonyl(C₁-C₆-alkyl)amino-C₁-C₆-alkyl,        -   xv) C₁-C₆-alkylcarbonylamino-C₁-C₆-alkyl,        -   xvi) C₁-C₆-alkylcarbonyl(C₁-C₆-alkyl)amino-C₁-C₆-alkyl,        -   xvii) halo-C₁-C₆-alkyl,        -   xviii) halo-C₁-C₆-alkoxy,        -   xix) halogen,        -   xx) hydroxy,        -   xxi) aminocarbonyl substituted on the nitrogen atom with            R_(N) and R_(O),        -   xxii) aminocarbonyl-C₁-C₆-alkoxy substituted on the nitrogen            atom with R_(N) and R_(O),        -   xxiii) heteroaryl substituted with one H, C₁-C₆-alkyl,            C₃-C₈-cycloalkyl, halo-C₁-C₆-alkyl, halo-C₁-C₆-alkoxy,            benzyl or aryl, wherein benzyl and aryl are substituted with            one to three substituents independently selected from H,            C₁-C₆-alkyl, C₃-C₈-cycloalkyl, halo-C₁-C₆-alkyl and            halo-C₁-C₆-alkoxy,        -   xxiv) heterocycloalkyl-C₁-C₆-alkoxy substituted with one H,            C₁-C₆-alkyl, C₃-C₈-cycloalkyl, halo-C₁-C₆-alkyl,            halo-C₁-C₆-alkoxy, benzyl or aryl, wherein benzyl and aryl            are substituted with one to three substituents independently            selected from H, C₁-C₆-alkyl, C₃-C₈-cycloalkyl,            halo-C₁-C₆-alkyl and halo-C₁-C₆-alkoxy, and        -   xxv) heterocycloalkyl-C₁-C₆-alkyl substituted with one H,            C₁-C₆-alkyl, C₃-C₈-cycloalkyl, halo-C₁-C₆-alkyl,            halo-C₁-C₆-alkoxy, benzyl or aryl, wherein benzyl and aryl            are substituted with one to three substituents independently            selected from H, C₁-C₆-alkyl, C₃-C₈-cycloalkyl,            halo-C₁-C₆-alkyl and halo-C₁-C₆-alkoxy:    -   R_(G1) and R_(G2) are independently selected from the group        consisting of        -   i) H,        -   ii) halogen,        -   iii) C₁-C₆-alkyl,        -   iv) C₃-C₈-cycloalkyl,        -   v) halo-C₁-C₆-alkoxy, and        -   vi) halo-C₁-C₆-alkyl;    -   R_(L) and R_(M) are independently selected from the group        consisting of        -   i) H, and        -   ii) C₁-C₆-alkyl;    -   R_(N) is selected from the group consisting of        -   i) H,        -   ii) C₁-C₆-alkoxy,        -   iii) C₁-C₆-alkoxy-C₁-C₆-alkyl,        -   iv) C₁-C₆-alkoxycarbonyl-C₁-C₆-alkyl,        -   v) C₁-C₆-alkyl,        -   vi) carboxy-C₁-C₆-alkyl,        -   vii) C₃-C₈-cycloalkyl,        -   viii) C₃-C₈-cycloalkyl-C₁-C₆-alkyl,        -   ix) hydroxy-C₁-C₆-alkyl,        -   x) phenyl, and        -   xi) heteroaryl-C₁-C₆-alkyl;    -   R_(O) is selected from the group consisting of        -   i) H, and        -   ii) C₁-C₆-alkyl;    -   or R_(N) and R_(O) together with the nitrogen atom to which they        are attached form a heterocycloalkyl;    -   or pharmaceutically acceptable salts.

Autotaxin (ATX) is a secreted enzyme also called ectonucleotidepyrophosphatase/phosphodiesterase 2 or lysophospholipase D that isimportant for converting lysophosphatidyl choline (LPC) to the bioactivesignaling molecule lysophosphatidic acid (LPA). It has been shown thatplasma LPA levels are well correlated with ATX activity and hence ATX isbelieved to be an important source of extracellular LPA. Earlyexperiments with a prototype ATX inhibitor have shown that such acompound is able to inhibit the LPA synthesizing activity in mouseplasma. Work conducted in the 1970s and early 1980s has demonstratedthat LPA can elicit a wide range of cellular responses; including smoothmuscle cell contraction, platelet activation, cell proliferation,chemotaxis and others. LPA mediates its effects via signaling to severalG protein coupled receptors (GPCRs); the first members were originallydenoted Edg (endothelial cell differentiation gene) receptors orventricular zone gene-1 (vzg-1) but are now called LPA receptors. Theprototypic group now consists of LPA1/Edg-2/VZG-1, LPA2/Edg-4, andLPA3/Edg-7. Recently, three additional LPA receptors LPA4/p2y9/GPR23,LPA5/GPR92 and LPA6/p2Y5 have been described that are more closelyrelated to nucleotide-selective purinergic receptors than to theprototypic LPA1-3 receptors. The ATX-LPA signaling axis is involved in alarge range of physiological and pathophysiological functions,including, for example, nervous system function, vascular development,cardiovascular physiology, reproduction, immune system function, chronicinflammation, tumor metastasis and progression, organ fibrosis as wellas obesity and/or other metabolic diseases such as diabetes mellitus.Therefore, increased activity of ATX and/or increased levels of LPA,altered LPA receptor expression and altered responses to LPA maycontribute to the initiation, progression and/or outcome of a number ofdifferent pathophysiological conditions related to the ATX/LPA axis.

In accordance with the invention, the compounds of formula (I) or theirpharmaceutically acceptable salts and esters can be used for thetreatment or prophylaxis of diseases, disorders or conditions that areassociated with the activity of autotaxin and/or the biological activityof lysophosphatidic acid (LPA).

The compounds of formula (I) or their pharmaceutically acceptable saltsand esters herein inhibit autotaxin activity and therefore inhibit LPAproduction and modulate LPA levels and associated signaling. Autotaxininhibitors described herein are useful as agents for the treatment orprevention of diseases or conditions in which ATX activity and/or LPAsignaling participates, is involved in the etiology or pathology of thedisease, or is otherwise associated with at least one symptom of thedisease. The ATX-LPA axis has been implicated for example inangiogenesis, chronic inflammation, autoimmune diseases, fibroticdiseases, cancer and tumor metastasis and progression, ocularconditions, metabolic conditions such as obesity and/or diabetesmellitus, conditions such as cholestatic or other forms of chronicpruritus as well as acute and chronic organ transplant rejection.

Objects of the present invention are the compounds of formula (I) andtheir aforementioned salts and esters and their use as therapeuticallyactive substances, a process for the manufacture of the said compounds,intermediates, pharmaceutical compositions, medicaments containing thesaid compounds, their pharmaceutically acceptable salts or esters, theuse of the said compounds, salts or esters for the treatment orprophylaxis of disorders or conditions that are associated with theactivity of ATX and/or the biological activity of lysophosphatidic acid(LPA), particularly in the treatment or prophylaxis of renal conditions,liver conditions, inflammatory conditions, conditions of the nervoussystem, conditions of the respiratory system, vascular andcardiovascular conditions, fibrotic diseases, cancer, ocular conditions,metabolic conditions, cholestatic and other forms of chronic pruritusand acute and—chronic organ transplant rejection, and the use of thesaid compounds, salts or esters for the production of medicaments forthe treatment or prophylaxis of renal conditions, liver conditions,inflammatory conditions, conditions of the nervous system, conditions ofthe respiratory system, vascular and cardiovascular conditions, fibroticdiseases, cancer, ocular conditions, metabolic conditions, cholestaticand other forms of chronic pruritus and acute and chronic organtransplant rejection. More particularly, the compounds of formula (I)and their aforementioned salts and esters and their use astherapeutically active substances, a process for the manufacture of thesaid compounds, intermediates, pharmaceutical compositions, medicamentscontaining the said compounds, their pharmaceutically acceptable saltsor esters, the use of the said compounds, salts or esters for thetreatment or prophylaxis of ocular conditions, furthermore particularlyglaucoma.

The term “C₁₋₆-alkoxy” denotes a group of the formula —O—R′, wherein R′is an C₁₋₆-alkyl group. Examples of C₁₋₆-alkoxy group include methoxy,ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy.Particular examples are methoxy and isopropoxy.

The term “C₁₋₆-alkoxy-C₁₋₆-alkyl” denotes a C₁₋₆-alkyl group wherein atleast one of the hydrogen atoms of the C₁₋₆-alkyl group is replaced by aC₁₋₆-alkoxy group. Particular examples are methoxymethyl, methoxyethyl,ethoxymethyl, ethoxyethyl, iso-propoxymethyl and iso-propoxyethyl.Particular example is methoxyethyl.

The term“C₁-C₆-alkoxy-C₁-C₆-alkylcarbonyl(C₁-C₆-alkyl)amino-C₁-C₆-alkyl” denotesan amino-C₁-C₆-alkyl wherein the nitrogen atom is substituted by aC₁-C₆-alkyl group and by a C₁-C₆-alkoxy-C₁-C₆-alkylcarbonyl group.Particular example is an aminomethyl wherein the nitrogen atom issubstituted by methyl and methoxymethylcarbonyl.

The term “C₁-C₆-alkoxy-C₁-C₆-alkylcarbonyl” denotes a group of theformula —C(O)—R′, wherein R′ is a C₁-C₆-alkoxy-C₁-C₆-alkyl group.Examples of C₁-C₆-alkoxy-C₁-C₆-alkylcarbonyl group include groupswherein R′ is methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl,iso-propoxymethyl and iso-propoxyethyl. Particular example is groupwherein R′ is methoxymethyl.

The term “C₁-C₆-alkoxy-C₁-C₆-alkylcarbonylamino-C₁-C₆-alkyl” denotes anamino-C₁-C₆-alkyl group wherein the nitrogen atom is substituted by Hand by a C₁-C₆-alkoxy-C₁-C₆-alkylcarbonyl group. Particular example isan aminomethyl wherein the nitrogen atom is substituted by H andmethoxymethylcarbonyl.

The term “C₁-C₆-alkoxycarbonyl-C₁-C₆-alkyl” denotes a C₁₋₆-alkyl groupwherein at least one of the hydrogen atoms of the C₁₋₆-alkyl group isreplaced by a C₁-C₆-alkoxycarbonyl group. Particular examples are groupswherein the C₁-C₆-alkoxycarbonyl group is methoxycarbonyl orethoxycarbonyl and the C₁₋₆-alkyl group is methyl or ethyl. Moreparticular examples are methoxyoxopropyl and ethoxyoxoethyl.

The term “C₁-C₆-alkoxycarbonyl” denotes a group of the formula —C(O)—R′,wherein R′ is a C₁-C₆-alkoxy group. Examples of C₁-C₆-alkoxycarbonylgroup include groups wherein R′ is methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, isobutoxy and tert-butoxy. Particular example aregroups wherein R′ is methoxy or tert-butoxy.

The term “C₁₋₆-alkyl” denotes a monovalent linear or branched saturatedhydrocarbon group of 1 to 6 carbon atoms. Examples of C₁₋₆-alkyl includemethyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl,tert-butyl and pentyl. Particular alkyl groups include methyl, isopropyland tert-butyl.

The term “C₁-C₆-alkylcarbonyl(C₁-C₆-alkyl)amino-C₁-C₆-alkyl” denotes anamino-C₁-C₆-alkyl wherein the nitrogen atom is substituted by aC₁-C₆-alkyl group and by a C₁-C₆-alkylcarbonyl group. Particular exampleis an aminomethyl wherein the nitrogen atom is substituted by methyl andmethylcarbonyl or ethylcarbonyl.

The term “C₁-C₆-alkylcarbonyl” denotes a group of the formula —C(O)—R′,wherein R′ is a C₁-C₆-alkyl group. Examples of C₁-C₆-alkylcarbonyl groupinclude groups wherein R′ is methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, isobutoxy and tert-butoxy. Particular example is group whereinR′ is methyl.

The term “C₁-C₆-alkylcarbonylamino-C₁-C₆-alkyl” denotes anamino-C₁-C₆-alkyl wherein the nitrogen atom is substituted by a H and bya C₁-C₆-alkylcarbonyl group. Particular example is an aminomethylwherein the nitrogen atom is substituted by H and methylcarbonyl orethylcarbonyl.

The term “C₁-C₆-alkylsulfonyl” denotes a group of the formula —S(O)₂—R′,wherein R′ is a C₁-C₆-alkyl group. Particular example is a group whereinR′ is methyl.

The term “C₁-C₆-alkylsulfonylamino” denotes a group of the formula—NH—S(O)₂—R′, wherein R′ is a C₁-C₆-alkyl group. Particular example is agroup wherein R′ is methyl.

The term “amino” denotes a —NH₂ group.

The term “aminoalkyl” denotes a C₁-C₆-alkyl group wherein one of thehydrogen atoms of the C₁₋₆-alkyl group is replaced by an amino group.Particular examples are aminomethyl, aminoethyl, aminopropyl andaminobutyl.

The term “aminocarbonyl” denotes a group of the formula —C(O)—NH₂.

The term “aminocarbonyl-C₁-C₆-alkoxy” denotes a C₁₋₆-alkoxy groupwherein one of the hydrogen atoms of the C₁₋₆-alkoxy group is replacedby an aminocarbonyl group. Particular example is a group wherein theC₁₋₆-alkoxy group is methoxy.

The term “aryl” denotes a phenyl or naphtyl group. Particular example isphenyl.

The term “carboxy” denotes a —COOH group.

The term “carboxy-C₁-C₆-alkyl” denotes a C₁₋₆-alkyl group wherein one ofthe hydrogen atoms of the C₁₋₆-alkyl group is replaced by a carboxygroup. Particular examples are carboxymethyl and carboxyethyl.

The term “cyano” denotes a —C≡N group.

The term “cyano-C₁-C₆-alkyl” denotes a C₁₋₆-alkyl group wherein one ofthe hydrogen atoms of the C₁₋₆-alkyl group is replaced by cyano group.Particular examples are cyanomethyl, cyanoethyl, cyanopropyl andcyanobutyl. Particular example is cyanopropyl.

The term “C₃₋₈-cycloalkoxy” denotes a group of the formula —O—R′,wherein R′ is a C₃₋₈-cycloalkyl. Particular example is a group whereinR′ is cyclopropyl.

The term “C₃₋₈-cycloalkyl” denotes a monovalent saturated monocyclic orbicyclic hydrocarbon group of 3 to 8 ring carbon atoms. Bicyclic means aring system consisting of two saturated carbocycles having two carbonatoms in common. Examples for monocyclic cycloalkyl are cyclopropyl,cyclobutanyl, cyclopentyl, cyclohexyl or cycloheptyl. Examples forbicyclic C₃₋₈-cycloalkyl are bicyclo[2.2.1]heptanyl orbicyclo[2.2.2]octanyl. Particular C₃₋₈-cycloalkyl group are cyclobutyl,cyclopropyl, cyclopentyl and cyclohexyl.

Particular example of “C₃₋₈-cycloalkyl” formed by the substituent R_(B)and R_(C) together with the carbon atoms to which they are attached arecyclopentyl or cyclohexyl, more particularly cyclopentyl.

The term “C₃₋₈-cycloalkyl-C₁₋₆-alkyl” denotes a C₁₋₆-alkyl group whereinat least one of the hydrogen atoms of the C₁₋₆-alkyl group is replacedby a C₃₋₈-cycloalkyl group. Particular example is cyclopropylmethyl.

The term “C₃-C₈-cycloalkylcarbonyl(C₁-C₆-alkyl)amino-C₁-C₆-alkyl”denotes an amino-C₁-C₆-alkyl wherein the nitrogen atom is substituted bya C₁-C₆-alkyl group and by a C₃-C₈-cycloalkylcarbonyl group. Particularexample is an aminomethyl wherein the nitrogen atom is substituted bymethyl and cyclopropylcarbonyl.

The term “C₃-C₈-cycloalkylcarbonyl” denotes a group of the formula—C(O)—R′, wherein R′ is a C₃-C₈-cycloalkyl group. Examples ofC₃-C₈-cycloalkylcarbonyl are groups wherein R′ is cyclopropyl.

The term “C₃-C₈-cycloalkylcarbonylamino-C₁-C₆-alkyl” denotes anamino-C₁-C₆-alkyl wherein the nitrogen atom is substituted by a H and bya C₃-C₈-cycloalkylcarbonyl group. Particular example is an aminomethylwherein the nitrogen atom is substituted by H and cyclopropylcarbonyl.

The term “C₃-C₈-cycloalkylsulfonyl” denotes a group of the formula—S(O)₂—R′, wherein R′ is a C₃-C₈-cycloalkyl group. Examples ofC₃-C₈-cycloalkylsulfonyl are groups wherein R′ is cyclopropyl.

The term “C₃-C₈-cycloalkylsulfonylamino” denotes a group of the formula—NH—S(O)₂—R′, wherein R′ is a C₃-C₈-cycloalkyl group. Examples ofC₃-C₈-cycloalkylsulfonyl are groups wherein R′ is cyclopropyl.

The term “dihydroxy-C₁-C₆-alkoxy” denotes a C₁₋₆-alkoxy group whereintwo of the hydrogen atoms of the dihydroxy-C₁-C₆-alkoxy group located ondifferent carbon atoms have been each replaced by an hydroxy group.Particular example is dihydroxypropoxy. Further particular example is2,3-dihydroxypropoxy.

The term “dihydroxy-C₁-C₆-alkyl” denotes a C₁₋₆-alkyl group wherein twoof the hydrogen atoms of the C₁₋₆-alkyl group located on differentcarbon atoms have been each replaced by an hydroxy group. Particularexample is dihydroxypropyl. Further particular example is2,3-dihydroxypropyl.

The term “dihydroxy-C₁-C₆-alkylamino” denotes a group of the formula—NH—R′, wherein R′ is a dihydroxy-C₁-C₆-alkyl group. Examples ofdihydroxy-C₁-C₆-alkylamino are groups wherein R′ is dihydroxypropyl,more particularly 2,3-dihydroxypropyl.

The term “dihydroxy-C₁-C₆-alkyl(C₁-C₆-alkyl)amino” denotes a group ofthe formula —NRR′, wherein R is a C₁-C₆-alkyl and R′ is adihydroxy-C₁-C₆-alkyl group. Examples ofdihydroxy-C₁-C₆-alkyl(C₁-C₆-alkyl)amino is dihydroxypropyl(methyl)amino,further particular example is 2,3-dihydroxypropyl(methyl)amino.

The term “halo-C₁₋₆-alkoxy” denotes a C₁₋₆-alkoxy group wherein at leastone of the hydrogen atoms of the C₁-C₆-alkoxy group has been replaced bythe same or different halogen atoms. Particular examples aredifluoromethoxy, trifluoromethoxy, difluoroethoxy and trifluoroethoxy.More particular example is trifluoromethoxy.

The term “halogen” and “halo” are used interchangeably herein and denotefluoro, chloro, bromo or iodo. Particular halogens are chloro andfluoro.

The term “halo-C₁₋₆-alkyl” denotes a C₁₋₆-alkyl group wherein at leastone of the hydrogen atoms of the C₁₋₆-alkyl group has been replaced bythe same or different halogen atoms. Particular examples aredifluoromethyl, trifluoromethyl, difluoroethyl and trifluoroethyl. Moreparticular example is trifluoromethyl.

The term “heteroaryl”, alone or in combination, denotes a monovalentaromatic heterocyclic mono- or bicyclic ring system of 5 to 12 ringatoms, comprising 1, 2, 3 or 4 heteroatoms selected from N, O and S, theremaining ring atoms being carbon. Examples of heteroaryl group includepyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl,oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl,pyridinyl, pyridazinyl, pyrimidinyl, triazinyl, azepinyl, diazepinyl,isoxazolyl, benzofuranyl, isothiazolyl, benzothienyl, indolyl,isoindolyl, isobenzofuranyl, benzimidazolyl, benzoxazolyl,benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzooxadiazolyl,benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl,quinazolinyl, quinoxalinyl, and benzothiophenyl. Particular heteroarylgroups are pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl,triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl,pyrazolyl, pyridazinyl, pyrimidinyl, isoxazolyl, isothiazolyl,benzofuranyl and benzothiophenyl. More particular heteroaryl groups arebenzoxazolonyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl,oxadiazolyl, pyrazinyl, pyrazolyl, pyridinyl and pyrimidinyl.

In the case of substituent R_(A), particular heteroaryl groups arebenzoxazolonyl, imidazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl,pyridinyl and pyrimidinyl. More particular examples are isoxazolyl andpyridinyl.

In the case of substituent R_(B), particular heteroaryl groups areoxadiaolyl, imidazolyl, 1,3,4-oxazolyl and 1,2,4-oxazolyl.

Particular example of heterocycloalkyl formed by the substitutent R_(B)and R_(C) together with the carbon atoms to which they are attached isthiazolyl.

In the case of substituent R_(G), particular heteroaryl groups areisoxazolyl, oxazolyl and pyrazolyl. More particular examples areisoxazolyl and pyrazolyl.

The term “heteroaryl-C₁-C₆-alkyl” denotes an alkyl group wherein one ofthe hydrogen atoms of the C₁-C₆-alkyl group has been replaced by aheteroaryl group.

In the case of substituent R_(N), particular heteroarylalkyl groups arepyridinylalkyl and thiophenylalkyl, more particularly pyridinylmethyland thiophenylmethyl.

The term “heterocycloalkyl”, alone or in combination, denotes amonovalent saturated or partly unsaturated mono- or bicyclic ring systemof 4 to 9 ring atoms, comprising 1, 2, or 3 ring heteroatoms selectedfrom N, O and S, the remaining ring atoms being carbon. Bicyclic meansconsisting of two cycles having two ring atoms in common, i.e. thebridge separating the two rings is either a single bond or a chain ofone or two ring atoms. Examples for monocyclic saturatedheterocycloalkyl are 4,5-dihydro-oxazolyl, oxetanyl, azetidinyl,pyrrolidinyl, 2-oxo-pyrrolidin-3-yl, tetrahydrofuranyl,tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl,isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl,tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl,1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, oroxazepanyl. Examples for bicyclic saturated heterocycloalkyl are8-aza-bicyclo[3.2.1]octyl, quinuclidinyl,8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl,3-oxa-9-aza-bicyclo[3.3.1]nonyl, or 3-thia-9-aza-bicyclo[3.3.1]nonyl.Examples for partly unsaturated heterocycloalkyl are dihydrofuryl,imidazolinyl, dihydro-oxazolyl, tetrahydro-pyridinyl, or dihydropyranyl.

In the case of substituent R₂, particular example of heterocycloalkyl ishydroxyazetidinyl, more particularly 3-hydroxyazetidin-1-yl.

In the case of substituent R_(A), particular example of heterocycloalkylis tetrahydropyranyl.

In the case of substitutent R_(B), particular example ofheterocycloalkyl is morpholinyl.

Particular example of heterocycloalkyl formed by the substitutent R_(N)and R_(O) together with the nitrogen atom to which they are attached arepiperidinyl, morpholinyl, pyrrolidinyl and methylpiperazinonyl.

The term “heterocycloalkyl-C₁₋₆-alkoxy” denotes a C₁₋₆-alkoxy groupwherein at least one of the hydrogen atoms of the alkyl group isreplaced by a heterocycloalkyl group. Particular examples aretetrahydropyranylmethoxy and tetrahydrofuranylnethoxy.

The term “heterocycloalkyl-C₁₋₆-alkyl” denotes a C₁₋₆-alkyl groupwherein at least one of the hydrogen atoms of the C₁₋₆-alkyl group isreplaced by a heterocycloalkyl group. Particular examples ofheterocycloalkyl-C₁₋₆-alkyl are groups wherein the heterocycloalkylgroup is methylpiperazinedionyl, pyrrolidinonyl and oxazolidinonyl andwherein the C₁₋₆-alkyl group is methyl.

The term “heterocycloalkylcarbonyl” denotes a group of the formula—C(O)—R′, wherein R′ is a heterocycloalkyl group. Example ofheterocycloalkylcarbonyl group are groups wherein R′ is4,5-dihydro-oxazolyl, oxetanyl, azetidinyl, pyrrolidinyl,2-oxo-pyrrolidin-3-yl, tetrahydrofuranyl, tetrahydro-thienyl,pyrazolidinyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl,isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl,tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl,1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, oroxazepanyl.

In the case of substituent R_(D3), particular examples ofheterocycloalkylcarbonyl group is group wherein R′ is pyrrolidinyl.

The term “hydroxy” denotes a —OH group.

The term “hydroxy-C₁₋₆-alkoxy” denotes a C₁₋₆-alkoxy group wherein oneof the hydrogen atoms of the C₁₋₆-alkoxy is replaced by a hydroxy group.Particular examples are hydroxyethoxy and hydroxypropoxy. Moreparticular examples is hydroxyethoxy.

The term “hydroxy-C₁₋₆-alkyl” denotes a C₁₋₆-alkyl group wherein one ofthe hydrogen atoms of the C₁₋₆-alkyl group is replaced by a hydroxygroup. Particular examples are hydroxymethyl and hydroxyethyl. Moreparticular example is hydroxyethyl.

The term “hydroxy-C₁-C₆-alkylamino” denotes a group of the formula—NH—R′, wherein R′ is an hydroxy-C₁-C₆-alkyl group. Examples ofhydroxy-C₁-C₆-alkylamino include groups wherein R′ is hydroxyethyl orhydroxypropyl. Particular example is a group wherein R′ is hydroxyethyl.

The term “hydroxy-C₁-C₆-alkyl(C₁-C₆-alkyl)amino” denotes a group of theformula —NRR′, wherein R is a C₁-C₆-alkyl and R′ is anhydroxy-C₁-C₆-alkyl group. Examples ofhydroxy-C₁-C₆-alkyl(C₁-C₆-alkyl)amino groups include groups wherein R ismethyl, ethyl, propyl or isopropyl and wherein R′ is hydroxyethyl orhydroxypropyl. Particular example is a group wherein R is methyl and R′is hydroxyethyl.

The term “trialkylsilyl-C₁-C₆-alkoxy-C₁-C₆-alkyl” denotes a C₁-C₆-alkylwherein one of the hydrogen atoms of the C₁₋₆-alkyl group is replaced bya trialkylsilyl-C₁-C₆-alkoxy. Particular example istrimethylsilylethoxymethyl.

The term “trialkylsilyl-C₁-C₆-alkoxy” denotes a C₁-C₆-alkoxy wherein oneof the hydrogen atoms of the C₁₋₆-alkoxy group is replaced by atrialkylsilyl. Particular example is trimethylsilylethoxyl.

The term “trialkylsilyl” denotes a group of formula —Si(R′)₃ whereineach R′ is an independently selected C₁-C₆-alkyl group. Particularexample are groups wherein R′ is methyl, ethyl, propyl, isopropyl,n-butyl, iso-butyl, sec-butyl, tert-butyl and pentyl. More particularexamples are groups wherein all R′ are identical, furthermoreparticularly wherein R′ is methyl.

The term “pharmaceutically acceptable salts” refers to those salts whichretain the biological effectiveness and properties of the free bases orfree acids, which are not biologically or otherwise undesirable. Thesalts are formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and thelike, in particular hydrochloric acid, and organic acids such as aceticacid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleicacid, malonic acid, succinic acid, fumaric acid, tartaric acid, citricacid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid,N-acetylcystein and the like. In addition, these salts may be preparedby addition of an inorganic base or an organic base to the free acid.Salts derived from an inorganic base include, but are not limited to,the sodium, potassium, lithium, ammonium, calcium, magnesium salts andthe like. Salts derived from organic bases include, but are not limitedto salts of primary, secondary, and tertiary amines, substituted aminesincluding naturally occurring substituted amines, cyclic amines andbasic ion exchange resins, such as isopropylamine, trimethylamine,diethylamine, triethylamine, tripropylamine, ethanolamine, lysine,arginine. N-ethylpiperidine, piperidine, polyimine resins and the like.Particular pharmaceutically acceptable salts of compounds of formula (I)are the hydrochloride salts, methanesulfonic acid salts and citric acidsalts.

“Pharmaceutically acceptable esters” means that compounds of generalformula (I) may be derivatised at functional groups to providederivatives which are capable of conversion back to the parent compoundsin vivo. Examples of such compounds include physiologically acceptableand metabolically labile ester derivatives, such as methoxymethylesters, methylthiomethyl esters and pivaloyloxymethyl esters.Additionally, any physiologically acceptable equivalents of thecompounds of general formula (I), similar to the metabolically labileesters, which are capable of producing the parent compounds of generalformula (I) in vivo, are within the scope of this invention.

The term “protecting group” (PG) denotes a group which selectivelyblocks a reactive site in a multifunctional compound such that achemical reaction can be carried out selectively at another unprotectedreactive site in the meaning conventionally associated with it insynthetic chemistry. Protecting groups can be removed at the appropriatepoint. Exemplary protecting groups are amino-protecting groups,carboxy-protecting groups or hydroxy-protecting groups. Particularprotecting groups are the tert-butoxycarbonyl (Boc), benzyloxycarbonyl(Cbz), fluorenylmethoxycarbonyl (Fmoc) and benzyl (Bn) groups. Furtherparticular protecting groups are the tert-butoxycarbonyl (Boc) and thefluorenylmethoxycarbonyl (Fmoc) groups. More particular protecting groupis the tert-butoxycarbonyl (Boc) group.

The abbreviation uM means microMolar and is equivalent to the symbol μM.

The abbreviation uL means microliter and is equivalent to the symbol μL.

The abbreviation ug means microgram and is equivalent to the symbol μg.

The compounds of formula (I) can contain several asymmetric centers andcan be present in the form of optically pure enantiomers, mixtures ofenantiomers such as, for example, racemates, optically purediastereoisomers, mixtures of diastereoisomers, diastereoisomericracemates or mixtures of diastereoisomeric racemates.

According to the Cahn-Ingold-Prelog Convention the asymmetric carbonatom can be of the “R” or “S” configuration.

Also an embodiment of the present invention provides compounds accordingto formula (I) as described herein and pharmaceutically acceptable saltsor esters thereof, in particular compounds according to formula (I) asdescribed herein and pharmaceutically acceptable salts thereof, moreparticularly compounds according to formula (I) as described herein.

A particular embodiment of the present invention provides compoundsaccording to formula (I) as described herein, wherein The presentinvention provides novel compounds of formula (I)

-   -   wherein    -   R_(A) is selected from the group consisting of        -   i) C₁-C₆-alkyl,        -   ii) cyano-C₁-C₆-alkyl,        -   iii) C₃-C₈-cycloalkyl,        -   iv) halo-C₁-C₆-alkoxy,        -   v) halo-C₁-C₆-alkyl,        -   vi) aryl substituted with R_(G), R_(G1) and R_(G2),        -   vii) heterocycloalkyl substituted with R_(G), R_(G1) and            R_(G2), and        -   viii) heteroaryl substituted with R_(G), R_(G1) and R_(G2);    -   R_(B) is selected from the group consisting of        -   i) C₁-C₆-alkyl,        -   ii) C₃-C₈-cycloalkyl,        -   iii) C₁-C₆-alkylsulfonyl,        -   iv) C₃-C₈-cycloalkylsulfonyl,        -   v) C₁-C₆-alkylsulfonylamino,        -   vi) C₃-C₈-cycloalkylsulfonylamino,        -   vii) aminocarbonyl,        -   viii) cyano,        -   ix) halogen,        -   x) halo-C₁-C₆-alkoxy,        -   xi) halo-C₁-C₆-alkyl,        -   xii) heterocycloalkyl, and        -   xiii) heteroaryl substituted with one H, C₁-C₆-alkyl or            trialkylsilyl-C₁-C₆-alkoxy-C₁-C₆-alkyl;    -   R_(C) and R_(C1) are independently selected from the group        consisting of        -   i) H,        -   ii) C₁-C₆-alkyl,        -   iii) C₃-C₈-cycloalkyl,        -   iv) halo-C₁-C₆-alkoxy,        -   v) halo-C₁-C₆-alkyl, and        -   vi) halogen;    -   or R_(B) and R_(C) together with the carbon atoms to which they        are attached form a ring system selected from the group        consisting of        -   i) C₃-C₈-cycloalkyl substituted with one to two substituent            independently selected from H, C₁-C₆-alkyl,            halo-C₁-C₆-alkoxy, halo-C₁-C₆-alkyl and C₃-C₈-cycloalkyl,        -   ii) heterocycloalkyl substituted with one to two substituent            independently selected from H, C₁-C₆-alkyl,            halo-C₁-C₆-alkoxy, halo-C₁-C₆-alkyl and C₃-C₈-cycloalkyl,        -   iii) aryl substituted with one to two substituent            independently selected from H, halogen, C₁-C₆-alkyl,            halo-C₁-C₆-alkoxy, halo-C₁-C₆-alkyl and C₃-C₈-cycloalkyl,            and        -   iv) heteroaryl substituted with one to two substituent            independently selected from H, halogen, C₁-C₆-alkyl,            halo-C₁-C₆-alkoxy, halo-C₁-C₆-alkyl and C₃-C₈-cycloalkyl;    -   W is selected from the ring systems A, B, C, D, E, F and G;

-   -   A¹, A³ and A⁴ are —CH— and A² is —CR_(D2)—,    -   A¹ is —N—, A² is —CR_(D2)—, A³ is —CH— or —N— and A⁴ is —CH—,    -   A¹, A³ and A⁴ are —CH— and A² is —N—,    -   A¹, A² and A⁴ are —CH— and A³ is —N—, or    -   A¹ and A³ are —CH—, A² is —CR_(D2)— and A⁴ is —N—;    -   one of A⁵ and A⁶ is —NR_(D3)— and the other one is        —CR_(L)R_(M)—;    -   R_(D1) is selected from the group consisting of        -   i) H,        -   ii) C₁-C₆-alkyl,        -   iii) halo-C₁-C₆-alkoxy,        -   iv) halo-C₁-C₆-alkyl, and        -   v) C₃-C₈-cycloalkyl;    -   R_(D2) is selected from the group consisting of        -   i) H,        -   ii) halogen,        -   iii) C₁-C₆-alkoxy-C₁-C₆-alkylcarbonyl,        -   iv) C₁-C₆-alkoxycarbonyl,        -   v) C₁-C₆-alkylcarbonyl,        -   vi) C₃-C₈-cycloalkylcarbonyl,        -   vii) C₁-C₆-alkyl,        -   viii) C₃-C₈-cycloalkyl,        -   ix) hydroxy-C₁-C₆-alkoxy,        -   x) hydroxy-C₁-C₆-alkyl(C₁-C₆-alkyl)amino,        -   xi) hydroxy-C₁-C₆-alkylamino,        -   xii) hydroxy-C₁-C₆-alkyl,        -   xiii) dihydroxy-C₁-C₆-alkoxy,        -   xiv) dihydroxy-C₁-C₆-alkyl(C₁-C₆-alkyl)amino,        -   xv) dihydroxy-C₁-C₆-alkylamino,        -   xvi) dihydroxy-C₁-C₆-alkyl,        -   xvii) halo-C₁-C₆-alkoxy,        -   xviii) halo-C₁-C₆-alkyl,        -   xix) heterocycloalkyl,        -   xx) heterocycloalkylcarbonyl, and        -   xxi) aminocarbonyl substituted on the nitrogen atom with one            to two independently selected C₁-C₆-alkyl;    -   R_(D3) is selected from the group consisting of        -   i) H,        -   ii) C₁-C₆-alkoxy-C₁-C₆-alkylcarbonyl,        -   iii) C₁-C₆-alkoxycarbonyl,        -   iv) C₁-C₆-alkylcarbonyl,        -   v) C₃-C₈-cycloalkylcarbonyl,        -   vi) C₁-C₆-alkyl,        -   vii) C₃-C₈-cycloalkyl,        -   viii) halo-C₁-C₆-alkoxy,        -   ix) halo-C₁-C₆-alkyl,        -   x) hydroxy-C₁-C₆-alkyl, and        -   xi) dihydroxy-C₁-C₆-alkyl,    -   R_(D4) is selected from the group consisting of        -   i) H,        -   ii) C₁-C₆-alkoxy-C₁-C₆-alkylcarbonyl,        -   iii) C₁-C₆-alkoxycarbonyl,        -   iv) C₁-C₆-alkylcarbonyl,        -   v) C₃-C₈-cycloalkylcarbonyl,        -   vi) C₁-C₆-alkyl,        -   vii) C₃-C₈-cycloalkyl,        -   viii) halo-C₁-C₆-alkoxy,        -   ix) halo-C₁-C₆-alkyl,        -   x) heterocycloalkylcarbonyl, and        -   xi) aminocarbonyl substituted on the nitrogen atom with one            to two independently selected C₁-C₆-alkyl;    -   R_(D5), R_(D6) and R_(D7) are independently selected from the        group consisting of        -   i) H,        -   ii) C₁-C₆-alkyl,        -   iii) C₁-C₆-alkoxy        -   iv) halo-C₁-C₆-alkoxy,        -   v) halo-C₁-C₆-alkyl,        -   vi) C₃-C₈-cycloalkyl, and        -   vii) C₃-C₈-cycloalkoxy;    -   R_(D4) is selected from the group consisting of        -   i) H,        -   ii) C₁-C₆-alkyl,        -   iii) C₁-C₆-alkoxy        -   iv) halo-C₁-C₆-alkoxy,        -   v) halo-C₁-C₆-alkyl.        -   vi) C₃-C₈-cycloalkyl,        -   vii) C₁-C₆-alkoxy-C₁-C₆-alkylcarbonyl,        -   viii) C₁-C₆-alkoxycarbonyl,        -   ix) C₁-C₆-alkylcarbonyl,        -   x) C₃-C₈-cycloalkylcarbonyl,        -   xi) heterocycloalkylcarbonyl, and        -   xii) aminocarbonyl substituted on the nitrogen atom with one            to two independently selected C₁-C₆-alkyl;    -   R_(G) is selected from the group consisting of        -   i) H,        -   ii) C₁-C₆-alkoxy,        -   iii) C₁-C₆-alkoxy-C₁-C₆-alkylcarbonylamino-C₁-C₆-alkyl,        -   iv)            C₁-C₆-alkoxy-C₁-C₆-alkylcarbonyl(C₁-C₆-alkyl)amino-C₁-C₆-alkyl,        -   v) C₁-C₆-alkoxycarbonyl,        -   vi) C₁-C₆-alkyl,        -   vii) C₁-C₆-alkylsulfonyl,        -   viii) C₃-C₈-cyloalkylsulfonyl,        -   ix) carboxy,        -   x) cyano,        -   xi) C₃-C₈-cycloalkyl,        -   xii) C₃-C₈-cycloalkoxy,        -   xiii) C₃-C₈-cycloalkylcarbonylamino-C₁-C₆-alkyl,        -   xiv) C₃-C₈-cycloalkylcarbonyl(C₁-C₆-alkyl)amino-C₁-C₆-alkyl,        -   xv) C₁-C₆-alkylcarbonylamino-C₁-C₆-alkyl,        -   xvi) C₁-C₆-alkylcarbonyl(C₁-C₆-alkyl)amino-C₁-C₆-alkyl,        -   xvii) halo-C₁-C₆-alkyl,        -   xviii) halo-C₁-C₆-alkoxy,        -   xix) halogen,        -   xx) hydroxy,        -   xxi) aminocarbonyl substituted on the nitrogen atom with            R_(N) and R_(O),        -   xxii) aminocarbonyl-C₁-C₆-alkoxy substituted on the nitrogen            atom with R_(N) and R_(O),        -   xxiii) heteroaryl substituted with one H, C₁-C₆-alkyl,            C₃-C₈-cycloalkyl, halo-C₁-C₆-alkyl, halo-C₁-C₆-alkoxy,            benzyl or aryl, wherein benzyl and aryl are substituted with            one to three substituents independently selected from H,            C₁-C₆-alkyl, C₃-C₈-cycloalkyl, halo-C₁-C₆-alkyl and            halo-C₁-C₆-alkoxy,        -   xxiv) heterocycloalkyl-C₁-C₆-alkoxy substituted with one H            C₁-C₆-alkyl, C₃-C₈-cycloalkyl, halo-C₁-C₆-alkyl,            halo-C₁-C₆-alkoxy, benzyl or aryl, wherein benzyl and aryl            are substituted with one to three substituents independently            selected from H, C₁-C₆-alkyl, C₃-C₈-cycloalkyl,            halo-C₁-C₆-alkyl and halo-C₁-C₆-alkoxy, and        -   xxv) heterocycloalkyl-C₁-C₆-alkyl substituted with one H,            C₁-C₆-alkyl, C₃-C₈-cycloalkyl, halo-C₁-C₆-alkyl,            halo-C₁-C₆-alkoxy, benzyl or aryl, wherein benzyl and aryl            are substituted with one to three substituents independently            selected from H, C₁-C₆-alkyl, C₃-C₈-cycloalkyl,            halo-C₁-C₆-alkyl and halo-C₁-C₆-alkoxy:    -   R_(G1) and R_(G2) are independently selected from the group        consisting of        -   i) H,        -   ii) halogen,        -   iii) C₁-C₆-alkyl,        -   iv) C₃-C₈-cycloalkyl,        -   v) halo-C₁-C₆-alkoxy, and        -   vi) halo-C₁-C₆-alkyl;    -   R_(L) and R_(M) are independently selected from the group        consisting of        -   i) H, and        -   ii) C₁-C₆-alkyl;    -   R_(N) is selected from the group consisting of        -   xii) H,        -   xiii) C₁-C₆-alkoxy,        -   xiv) C₁-C₆-alkoxy-C₁-C₆-alkyl,        -   xv) C₁-C₆-alkoxycarbonyl-C₁-C₆-alkyl,        -   xvi) C₁-C₆-alkyl,        -   xvii) carboxy-C₁-C₆-alkyl,        -   xviii) C₃-C₈-cycloalkyl,        -   xix) C₃-C₈-cycloalkyl-C₁-C₆-alkyl,        -   xx) hydroxy-C₁-C₆-alkyl,        -   xxi) phenyl, and        -   xxii) heteroaryl-C₁-C₆-alkyl;    -   R_(O) is selected from the group consisting of        -   i) H, and        -   ii) C₁-C₆-alkyl;    -   or R_(N) and R_(O) together with the nitrogen atom to which they        are attached form a heterocycloalkyl;    -   or pharmaceutically acceptable salts.

In another embodiment, the present invention provides novel compounds offormula (I)

-   -   wherein    -   R_(A) is selected from the group consisting of        -   i) C₁-C₆-alkyl,        -   ii) cyano-C₁-C₆-alkyl,        -   iii) C₃-C₈-cycloalkyl,        -   iv) halo-C₁-C₆-alkoxy,        -   v) halo-C₁-C₆-alkyl,        -   vi) aryl substituted with R_(G), R_(G1) and R_(G2),        -   vii) heterocycloalkyl substituted with R_(G), R_(G1) and            R_(G2), and        -   viii) heteroaryl substituted with R_(G), R_(G1) and R_(G2);    -   R_(B) is selected from the group consisting of        -   i) C₁-C₆-alkyl,        -   ii) C₃-C₈-cycloalkyl,        -   iii) C₁-C₆-alkylsulfonyl,        -   iv) C₃-C₈-cycloalkylsulfonyl,        -   v) C₁-C₆-alkylsulfonylamino,        -   vi) C₃-C₈-cycloalkylsulfonylamino,        -   vii) aminocarbonyl,        -   viii) cyano,        -   ix) halogen,        -   x) halo-C₁-C₆-alkoxy,        -   xi) halo-C₁-C₆-alkyl,        -   xii) heterocycloalkyl, and        -   xiii) heteroaryl substituted with one H, C₁-C₆-alkyl or            trialkylsilyl-C₁-C₆-alkoxy-C₁-C₆-alkyl;    -   R_(C) and R_(C1) are independently selected from the group        consisting of        -   i) H,        -   ii) C₁-C₆-alkyl,        -   iii) C₃-C₈-cycloalkyl,        -   iv) halo-C₁-C₆-alkoxy,        -   v) halo-C₁-C₆-alkyl, and        -   vi) halogen;    -   or R_(B) and R_(C) together with the carbon atoms to which they        are attached form a ring system selected from the group        consisting of        -   i) C₃-C₈-cycloalkyl substituted with one to two substituent            independently selected from H, C₁-C₆-alkyl,            halo-C₁-C₆-alkoxy, halo-C₁-C₆-alkyl and C₃-C₈-cycloalkyl,        -   ii) heterocycloalkyl substituted with one to two substituent            independently selected from H, C₁-C₆-alkyl,            halo-C₁-C₆-alkoxy, halo-C₁-C₆-alkyl and C₃-C₈-cycloalkyl,        -   iii) aryl substituted with one to two substituent            independently selected from H, halogen. C₁-C₆-alkyl,            halo-C₁-C₆-alkoxy, halo-C₁-C₆-alkyl and C₃-C₈-cycloalkyl,            and        -   iv) heteroaryl substituted with one to two substituent            independently selected from H, halogen, C₁-C₆-alkyl,            halo-C₁-C₆-alkoxy, halo-C₁-C₆-alkyl and C₃-C₈-cycloalkyl;    -   W is selected from the ring systems A, B, C, D and E;

-   -   A¹, A³ and A⁴ are —CH— and A² is —CR_(D2)—,    -   A¹ is —N—, A² is —CR_(D2)—, A³ is —CH— or —N— and A⁴ is —CH—,    -   A¹, A³ and A⁴ are —CH— and A² is —N—,    -   A¹, A² and A⁴ are —CH— and A³ is —N—, or    -   A¹ and A³ are —CH—, A is —CR_(D2)— and A⁴ is —N—;    -   one of A⁵ and A⁶ is —NR_(D3)— and the other one is        —CR_(L)R_(M)—;    -   R_(D1) is selected from the group consisting of        -   i) H,        -   ii) C₁-C₆-alkyl,        -   iii) halo-C₁-C₆-alkoxy,        -   iv) halo-C₁-C₆-alkyl, and        -   v) C₃-C₈-cycloalkyl;    -   R_(D2) is selected from the group consisting of        -   i) H,        -   ii) halogen,        -   iii) C₁-C₆-alkoxy-C₁-C₆-alkylcarbonyl,        -   iv) C₁-C₆-alkoxycarbonyl,        -   v) C₁-C₆-alkylcarbonyl,        -   vi) C₃-C₈-cycloalkylcarbonyl,        -   vii) C₁-C₆-alkyl,        -   viii) C₃-C₈-cycloalkyl,        -   ix) hydroxy-C₁-C₆-alkoxy,        -   x) hydroxy-C₁-C₆-alkyl(C₁-C₆-alkyl)amino,        -   xi) hydroxy-C₁-C₆-alkylamino,        -   xii) hydroxy-C₁-C₆-alkyl,        -   xiii) dihydroxy-C₁-C₆-alkoxy,        -   xiv) dihydroxy-C₁-C₆-alkyl(C₁-C₆-alkyl)amino,        -   xv) dihydroxy-C₁-C₆-alkylamino,        -   xvi) dihydroxy-C₁-C₆-alkyl,        -   xvii) halo-C₁-C₆-alkoxy,        -   xviii) halo-C₁-C₆-alkyl,        -   xix) heterocycloalkyl,        -   xx) heterocycloalkylcarbonyl, and        -   xxi) aminocarbonyl substituted on the nitrogen atom with one            to two independently selected C₁-C₆-alkyl;    -   R_(D3) is selected from the group consisting of        -   i) H,        -   ii) C₁-C₆-alkoxy-C₁-C₆-alkylcarbonyl,        -   iii) C₁-C₆-alkoxycarbonyl,        -   iv) C₁-C₆-alkylcarbonyl,        -   v) C₃-C₈-cycloalkylcarbonyl,        -   vi) C₁-C₆-alkyl,        -   vii) C₃-C₈-cycloalkyl,        -   viii) halo-C₁-C₆-alkoxy,        -   ix) halo-C₁-C₆-alkyl,        -   x) hydroxy-C₁-C₆-alkyl, and        -   xi) dihydroxy-C₁-C₆-alkyl.    -   R_(D4) is selected from the group consisting of        -   i) H,        -   ii) C₁-C₆-alkoxy-C₁-C₆-alkylcarbonyl,        -   iii) C₁-C₆-alkoxycarbonyl,        -   iv) C₁-C₆-alkylcarbonyl,        -   v) C₃-C₈-cycloalkylcarbonyl,        -   vi) C₁-C₆-alkyl,        -   vii) C₃-C₈-cycloalkyl,        -   viii) halo-C₁-C₆-alkoxy,        -   ix) halo-C₁-C₆-alkyl,        -   x) heterocycloalkylcarbonyl, and        -   xi) aminocarbonyl substituted on the nitrogen atom with one            to two independently selected C₁-C₆-alkyl;    -   R_(D5), R_(D6) and R_(D7) are independently selected from the        group consisting of        -   i) H,        -   ii) C₁-C₆-alkyl,        -   iii) C₁-C₆-alkoxy        -   iv) halo-C₁-C₆-alkoxy,        -   v) halo-C₁-C₆-alkyl,        -   vi) C₃-C₈-cycloalkyl, and        -   vii) C₃-C₈-cycloalkoxy,    -   R_(G) is selected from the group consisting of        -   i) H,        -   ii) C₁-C₆-alkoxy,        -   iii) C₁-C₆-alkoxy-C₁-C₆-alkylcarbonylamino-C₁-C₆-alkyl,        -   iv)            C₁-C₆-alkoxy-C₁-C₆-alkylcarbonyl(C₁-C₆-alkyl)amino-C₁-C₆-alkyl,        -   v) C₁-C₆-alkoxycarbonyl,        -   vi) C₁-C₆-alkyl,        -   vii) C₁-C₆-alkylsulfonyl,        -   viii) C₃-C₈-cyloalkylsulfonyl,        -   ix) carboxy,        -   x) cyano,        -   xi) C₃-C₈-cycloalkyl,        -   xii) C₃-C₈-cycloalkoxy,        -   xiii) C₃-C₈-cycloalkylcarbonylamino-C₁-C₆-alkyl,        -   xiv) C₃-C₈-cycloalkylcarbonyl(C₁-C₆-alkyl)amino-C₁-C₆-alkyl,        -   xv) C₁-C₆-alkylcarbonylamino-C₁-C₆-alkyl,        -   xvi) C₁-C₆-alkylcarbonyl(C₁-C₆-alkyl)amino-C₁-C₆-alkyl,        -   xvii) halo-C₁-C₆-alkyl,        -   xviii) halo-C₁-C₆-alkoxy,        -   xix) halogen,        -   xx) aminocarbonyl substituted on the nitrogen atom with            R_(N) and R_(O),        -   xxi) aminocarbonyl-C₁-C₆-alkoxy substituted on the nitrogen            atom with R_(N) and R_(O),        -   xxii) heteroaryl substituted with one H, C₁-C₆-alkyl,            C₃-C₈-cycloalkyl, halo-C₁-C₆-alkyl, halo-C₁-C₆-alkoxy,            benzyl or aryl, wherein benzyl and aryl are substituted with            one to three substituents independently selected from H,            C₁-C₆-alkyl, C₃-C₈-cycloalkyl, halo-C₁-C₆-alkyl and            halo-C₁-C₆-alkoxy,        -   xxiii) heterocycloalkyl-C₁-C₆-alkoxy substituted with one H,            C₁-C₆-alkyl, C₃-C₈-cycloalkyl, halo-C₁-C₆-alkyl,            halo-C₁-C₆-alkoxy, benzyl or aryl, wherein benzyl and aryl            are substituted with one to three substituents independently            selected from H C₁-C₆-alkyl, C₃-C₈-cycloalkyl,            halo-C₁-C₆-alkyl and halo-C₁-C₆-alkoxy, and        -   xxiv) heterocycloalkyl-C₁-C₆-alkyl substituted with one H,            C₁-C₆-alkyl, C₃-C₈-cycloalkyl, halo-C₁-C₆-alkyl,            halo-C₁-C₆-alkoxy, benzyl or aryl, wherein benzyl and aryl            are substituted with one to three substituents independently            selected from H, C₁-C₆-alkyl. C₃-C₈-cycloalkyl,            halo-C₁-C₆-alkyl and halo-C₁-C₆-alkoxy;    -   R_(G1) and R_(G2) are independently selected from the group        consisting of        -   i) H,        -   ii) halogen,        -   iii) C₁-C₆-alkyl,        -   iv) C₃-C₈-cycloalkyl,        -   v) halo-C₁-C₆-alkoxy, and        -   vi) halo-C₁-C₆-alkyl:    -   R_(L) and R_(M) are independently selected from the group        consisting of        -   i) H, and        -   ii) C₁-C₆-alkyl;    -   R_(N) is selected from the group consisting of        -   i) H,        -   ii) C₁-C₆-alkoxy,        -   iii) C₁-C₆-alkoxy-C₁-C₆-alkyl,        -   iv) C₁-C₆-alkoxycarbonyl-C₁-C₆-alkyl,        -   v) C₁-C₆-alkyl,        -   vi) carboxy-C₁-C₆-alkyl,        -   vii) C₃-C₈-cycloalkyl,        -   viii) C₃-C₈-cycloalkyl-C₁-C₆-alkyl,        -   ix) hydroxy-C₁-C₆-alkyl,        -   x) phenyl, and        -   xi) heteroaryl-C₁-C₆-alkyl;    -   R_(O) is selected from the group consisting of        -   i) H, and        -   ii) C₁-C₆-alkyl;    -   or R_(N) and R_(O) together with the nitrogen atom to which they        are attached form a heterocycloalkyl;    -   or pharmaceutically acceptable salts.

A particular embodiment of the present invention provides compoundsaccording to formula (I) as described herein, wherein

-   -   R_(A) is selected from the group consisting of        -   i) C₁-C₆-alkyl,        -   ii) cyano-C₁-C₆-alkyl,        -   iii) C₃-C₈-cycloalkyl,        -   iv) aryl substituted with R_(G) and R_(G1),        -   v) heterocycloalkyl substituted with R_(G) and R_(G1), and        -   vi) heteroaryl substituted with R_(G) and R_(G1);    -   R_(B) is selected from the group consisting of        -   i) C₁-C₆-alkyl,        -   ii) C₁-C₆-alkylsulfonyl,        -   iii) C₁-C₆-alkylsulfonylamino,        -   iv) aminocarbonyl,        -   v) cyano,        -   vi) halogen,        -   vii) heterocycloalkyl, and        -   viii) heteroaryl substituted with one H, C₁-C₆-alkyl or            trialkylsilyl-C₁-C₆-alkoxy-C₁-C₆-alkyl;    -   R_(C1) is H and R_(C) is selected from the group consisting of        -   i) H,        -   ii) C₁-C₆-alkyl, and        -   iii) halogen;    -   or R_(B) and R_(C) together with the carbon atoms to which they        are attached form a ring system selected from the group        consisting of        -   i) heterocycloalkyl substituted with one to two substituent            independently selected from H and C₁-C₆-alkyl, and        -   ii) heteroaryl substituted with one to two substituent            independently selected from H and C₁-C₆-alkyl;    -   W is selected from the ring systems A, B, C, D and E;

-   -   A¹, A³ and A⁴ are —CH— and A² is —CR_(D2)—,    -   A¹ is —N—, A² is —CR_(D2)—, A³ is —CH— or —N— and A⁴ is —CH—,    -   A¹, A³ and A⁴ are —CH— and A² is —N—, or    -   A¹ and A³ are —CH—, A² is —CR_(D2)— and A⁴ is —N—;    -   one of A⁵ and A⁶ is —NR_(D3)— and the other one is        —CR_(L)R_(M)—;    -   R_(D1) is C₁-C₆-alkyl;    -   R_(D2) is selected from the group consisting of        -   i) H,        -   ii) halogen,        -   iii) hydroxy-C₁-C₆-alkoxy,        -   iv) hydroxy-C₁-C₆-alkyl(C₁-C₆-alkyl)amino,        -   v) hydroxy-C₁-C₆-alkylamino,        -   vi) dihydroxy-C₁-C₆-alkoxy,        -   vii) dihydroxy-C₁-C₆-alkyl(C₁-C₆-alkyl)amino, and        -   viii) heterocycloalkyl;    -   R_(D3) is selected from the group consisting of        -   i) H,        -   ii) C₁-C₆-alkoxy-C₁-C₆-alkylcarbonyl,        -   iii) C₁-C₆-alkoxycarbonyl, and        -   iv) C₁-C₆-alkylcarbonyl;    -   R_(D4) is selected from the group consisting of        -   i) H,        -   ii) C₁-C₆-alkoxycarbonyl,        -   iii) heterocycloalkylcarbonyl,        -   iv) aminocarbonyl substituted on the nitrogen atom with one            to two independently selected C₁-C₆-alkyl, and        -   v) aryl substituted with one to three substituents            independently selected from H, C₁-C₆-alkyl.            C₃-C₈-cycloalkyl, halo-C₁-C₆-alkyl and halo-C₁-C₆-alkoxy:    -   R_(G) is selected from the group consisting of        -   i) H,        -   ii) C₁-C₆-alkoxy,        -   iii) C₁-C₆-alkoxy-C₁-C₆-alkylcarbonylamino-C₁-C₆-alkyl,        -   iv)            C₁-C₆-alkoxy-C₁-C₆-alkylcarbonyl(C₁-C₆-alkyl)amino-C₁-C₆-alkyl,        -   v) C₁-C₆-alkoxycarbonyl,        -   vi) C₁-C₆-alkyl,        -   vii) C₁-C₆-alkylsulfonyl,        -   viii) carboxy,        -   ix) cyano,        -   x) C₃-C₈-cycloalkoxy,        -   xi) C₃-C₈-cycloalkylcarbonylamino-C₁-C₆-alkyl,        -   xii) C₃-C₈-cycloalkylcarbonyl(C₁-C₆-alkyl)amino-C₁-C₆-alkyl,        -   xiii) halo-C₁-C₆-alkyl,        -   xiv) halogen,        -   xv) hydroxy,        -   xvi) aminocarbonyl substituted on the nitrogen atom with            R_(N) and R_(O),        -   xvii) aminocarbonyl-C₁-C₆-alkoxy substituted on the nitrogen            atom with R_(N) and R_(O),        -   xviii) heteroaryl substituted with one H or C₁-C₆-alkyl,        -   xix) heterocycloalkyl-C₁-C₆-alkoxy substituted with one H or            C₁-C₆-alkyl, and        -   xx) heterocycloalkyl-C₁-C₆-alkyl substituted with one H or            C₁-C₆-alkyl;    -   R_(G1) and R_(G2) are independently selected from the group        consisting of        -   i) H,        -   ii) halogen,        -   iii) C₁-C₆-alkyl, and        -   iv) halo-C₁-C₆-alkoxy;    -   R_(L) and R_(M) are H;    -   R_(N) is selected from the group consisting of        -   i) H,        -   ii) C₁-C₆-alkoxy,        -   iii) C₁-C₆-alkoxy-C₁-C₆-alkyl,        -   iv) C₁-C₆-alkoxycarbonyl-C₁-C₆-alkyl,        -   v) C₁-C₆-alkyl,        -   vi) carboxy-C₁-C₆-alkyl,        -   vii) C₃-C₈-cycloalkyl,        -   viii) C₃-C₈-cycloalkyl-C₁-C₆-alkyl,        -   ix) hydroxy-C₁-C₆-alkyl,        -   x) phenyl, and        -   xi) heteroaryl-C₁-C₆-alkyl;    -   R_(O) is selected from the group consisting of        -   i) H, and        -   ii) C₁-C₆-alkyl;    -   or R_(N) and R_(O) together with the nitrogen atom to which they        are attached form a heterocycloalkyl;    -   or pharmaceutically acceptable salts.

A particular embodiment of the present invention provides compoundsaccording to formula (I) as described herein, wherein

-   -   R_(A) is selected from the group consisting of        -   i) C₁-C₆-alkyl,        -   ii) cyano-C₁-C₆-alkyl,        -   iii) C₃-C₈-cycloalkyl,        -   iv) aryl substituted with R_(G) and R_(G1),        -   v) heterocycloalkyl substituted with R_(G) and R_(G1), and        -   vi) heteroaryl substituted with R_(G) and R_(G1);    -   R_(B) is selected from the group consisting of        -   i) C₁-C₆-alkyl,        -   ii) C₁-C₆-alkylsulfonyl,        -   iii) C₁-C₆-alkylsulfonylamino,        -   iv) aminocarbonyl,        -   v) cyano,        -   vi) halogen,        -   vii) heterocycloalkyl, and        -   viii) heteroaryl substituted with one H, C₁-C₆-alkyl or            trialkylsilyl-C₁-C₆-alkoxy-C₁-C₆-alkyl;    -   R_(C1) is H and R_(C) is selected from the group consisting of        -   i) H,        -   ii) C₁-C₆-alkyl, and        -   iii) halogen;    -   or R_(B) and R_(C) together with the carbon atoms to which they        are attached form a ring system selected from the group        consisting of        -   i) heterocycloalkyl substituted with one to two substituent            independently selected from H and C₁-C₆-alkyl, and        -   ii) heteroaryl substituted with one to two substituent            independently selected from H and C₁-C₆-alkyl;    -   W is selected from the ring systems A, B, C, D and E;

-   -   A¹, A³ and A⁴ are —CH— and A² is —CR_(D2)—,    -   A¹ is —N—, A² is —CR_(D2)—, A³ is —CH— or —N— and A⁴ is —CH—,    -   A¹, A³ and A⁴ are —CH— and A² is —N—, or    -   A¹ and A³ are —CH—, A is —CR_(D2)— and A⁴ is —N—;    -   one of A⁵ and A⁶ is —NR_(D3)— and the other one is        —CR_(L)R_(M)—;    -   R_(D1) is C₁-C₆-alkyl;    -   R_(D2) is selected from the group consisting of        -   i) H,        -   ii) halogen,        -   iii) hydroxy-C₁-C₆-alkoxy,        -   iv) hydroxy-C₁-C₆-alkyl(C₁-C₆-alkyl)amino,        -   v) hydroxy-C₁-C₆-alkylamino,        -   vi) dihydroxy-C₁-C₆-alkoxy,        -   vii) dihydroxy-C₁-C₆-alkyl(C₁-C₆-alkyl)amino, and        -   viii) heterocycloalkyl;    -   R_(D3) is selected from the group consisting of        -   i) H,        -   ii) C₁-C₆-alkoxy-C₁-C₆-alkylcarbonyl,        -   iii) C₁-C₆-alkoxycarbonyl, and        -   iv) C₁-C₆-alkylcarbonyl;    -   R_(D4) is selected from the group consisting of        -   i) H,        -   ii) C₁-C₆-alkoxycarbonyl,        -   iii) heterocycloalkylcarbonyl, and        -   iv) aminocarbonyl substituted on the nitrogen atom with one            to two independently selected C₁-C₆-alkyl;    -   R_(G) is selected from the group consisting of        -   i) H,        -   ii) C₁-C₆-alkoxy,        -   iii) C₁-C₆-alkoxy-C₁-C₆-alkylcarbonylamino-C₁-C₆-alkyl,        -   iv)            C₁-C₆-alkoxy-C₁-C₆-alkylcarbonyl(C₁-C₆-alkyl)amino-C₁-C₆-alkyl,        -   v) C₁-C₆-alkoxycarbonyl,        -   vi) C₁-C₆-alkyl,        -   vii) C₁-C₆-alkylsulfonyl,        -   viii) carboxy,        -   ix) cyano,        -   x) C₃-C₈-cycloalkoxy,        -   xi) C₃-C₈-cycloalkylcarbonylamino-C₁-C₆-alkyl,        -   xii) C₃-C₈-cycloalkylcarbonyl(C₁-C₆-alkyl)amino-C₁-C₆-alkyl,        -   xiii) halo-C₁-C₆-alkyl,        -   xiv) halogen,        -   xv) hydroxy,        -   xvi) aminocarbonyl substituted on the nitrogen atom with            R_(N) and R_(O),        -   xvii) aminocarbonyl-C₁-C₆-alkoxy substituted on the nitrogen            atom with R_(N) and R_(O),        -   xviii) heteroaryl substituted with one H or C₁-C₆-alkyl,        -   xix) heterocycloalkyl-C₁-C₆-alkoxy substituted with one H or            C₁-C₆-alkyl, and        -   xx) heterocycloalkyl-C₁-C₆-alkyl substituted with one H or            C₁-C₆-alkyl;    -   R_(G1) and R_(G2) are independently selected from the group        consisting of        -   i) H,        -   ii) halogen,        -   iii) C₁-C₆-alkyl, and        -   iv) halo-C₁-C₆-alkoxy;    -   R_(L) and R_(M) are H;    -   R_(N) is selected from the group consisting of        -   xii) H,        -   xiii) C₁-C₆-alkoxy,        -   xiv) C₁-C₆-alkoxy-C₁-C₆-alkyl,        -   xv) C₁-C₆-alkoxycarbonyl-C₁-C₆-alkyl,        -   xvi) C₁-C₆-alkyl,        -   xvii) carboxy-C₁-C₆-alkyl,        -   xviii) C₃-C₈-cycloalkyl,        -   xix) C₃-C₈-cycloalkyl-C₁-C₆-alkyl,        -   xx) hydroxy-C₁-C₆-alkyl,        -   xxi) phenyl, and        -   xxii) heteroaryl-C₁-C₆-alkyl;    -   R_(O) is selected from the group consisting of        -   i) H, and        -   ii) C₁-C₆-alkyl;    -   or R_(N) and R_(O) together with the nitrogen atom to which they        are attached form a heterocycloalkyl;    -   or pharmaceutically acceptable salts.

A particular embodiment of the present invention provides compoundsaccording to formula (I) as described herein, wherein

-   -   R_(A) is selected from the group consisting of        -   i) C₁-C₆-alkyl,        -   ii) cyano-C₁-C₆-alkyl,        -   iii) C₃-C₈-cycloalkyl,        -   iv) aryl substituted with R_(G) and R_(G1),        -   v) heterocycloalkyl substituted with R_(G) and R_(G1), and        -   vi) heteroaryl substituted with R_(G) and R_(G1);    -   R_(B) is selected from the group consisting of        -   i) C₁-C₆-alkyl,        -   ii) C₁-C₆-alkylsulfonyl,        -   iii) C₁-C₆-alkylsulfonylamino,        -   iv) aminocarbonyl,        -   v) cyano,        -   vi) halogen,        -   vii) heterocycloalkyl, and        -   viii) heteroaryl substituted with one H, C₁-C₆-alkyl or            trialkylsilyl-C₁-C₆-alkoxy-C₁-C₆-alkyl;    -   R_(C1) is H and R_(C) is selected from the group consisting of        -   i) H,        -   ii) C₁-C₆-alkyl, and        -   iii) halogen;    -   or R_(B) and R_(C) together with the carbon atoms to which they        are attached form a ring system selected from the group        consisting of        -   i) heterocycloalkyl substituted with one to two substituent            independently selected from H and C₁-C₆-alkyl, and        -   ii) heteroaryl substituted with one to two substituent            independently selected from H and C₁-C₆-alkyl;    -   W is selected from the ring systems A, B, C, D and E;

-   -   A¹, A³ and A⁴ are —CH— and A² is —CR_(D2)—,    -   A¹ is —N—, A² is —CR_(D2)—, A³ is —CH— or —N— and A⁴ is —CH—,    -   A¹, A³ and A⁴ are —CH— and A² is —N—, or    -   A¹ and A³ are —CH—, A is —CR_(D2)— and A⁴ is —N—;    -   one of A⁵ and A⁶ is —NR_(D3)— and the other one is        —CR_(L)R_(M)—;    -   R_(D1) is C₁-C₆-alkyl;    -   R_(D2) is selected from the group consisting of        -   i) H,        -   ii) halogen,        -   iii) hydroxy-C₁-C₆-alkoxy,        -   iv) hydroxy-C₁-C₆-alkyl(C₁-C₆-alkyl)amino,        -   v) hydroxy-C₁-C₆-alkylamino,        -   vi) dihydroxy-C₁-C₆-alkoxy,        -   vii) dihydroxy-C₁-C₆-alkyl(C₁-C₆-alkyl)amino, and        -   viii) heterocycloalkyl;    -   R_(D3) is selected from the group consisting of        -   i) H,        -   ii) C₁-C₆-alkoxy-C₁-C₆-alkylcarbonyl,        -   iii) C₁-C₆-alkoxycarbonyl, and        -   iv) C₁-C₆-alkylcarbonyl;    -   R_(D4) is selected from the group consisting of        -   i) H,        -   ii) C₁-C₆-alkoxycarbonyl,        -   iii) heterocycloalkylcarbonyl, and        -   iv) aminocarbonyl substituted on the nitrogen atom with one            to two independently selected C₁-C₆-alkyl;    -   R_(G) is selected from the group consisting of        -   i) H,        -   ii) C₁-C₆-alkoxy,        -   iii) C₁-C₆-alkoxy-C₁-C₆-alkylcarbonylamino-C₁-C₆-alkyl,        -   iv)            C₁-C₆-alkoxy-C₁-C₆-alkylcarbonyl(C₁-C₆-alkyl)amino-C₁-C₆-alkyl,        -   v) C₁-C₆-alkoxycarbonyl,        -   vi) C₁-C₆-alkyl,        -   vii) C₁-C₆-alkylsulfonyl,        -   viii) carboxy,        -   ix) cyano,        -   x) C₃-C₈-cycloalkoxy,        -   xi) C₃-C₈-cycloalkylcarbonylamino-C₁-C₆-alkyl,        -   xii) C₃-C₈-cycloalkylcarbonyl(C₁-C₆-alkyl)amino-C₁-C₆-alkyl,        -   xiii) halo-C₁-C₆-alkyl,        -   xiv) halogen,        -   xv) aminocarbonyl substituted on the nitrogen atom with            R_(N) and R_(O),        -   xvi) aminocarbonyl-C₁-C₆-alkoxy substituted on the nitrogen            atom with R_(N) and R_(O),        -   xvii) heteroaryl substituted with one H or C₁-C₆-alkyl,        -   xviii) heterocycloalky-C₁-C₆-alkoxy substituted with one H            or C₁-C₆-alkyl, and        -   xix) heterocycloalkyl-C₁-C₆-alkyl substituted with one H or            C₁-C₆-alkyl:    -   R_(G1) and R_(G2) are independently selected from the group        consisting of        -   i) H,        -   ii) halogen,        -   iii) C₁-C₆-alkyl, and        -   iv) halo-C₁-C₆-alkoxy;    -   R_(L) and R_(M) are H;    -   R_(N) is selected from the group consisting of        -   i) H,        -   ii) C₁-C₆-alkoxy,        -   iii) C₁-C₆-alkoxy-C₁-C₆-alkyl,        -   iv) C₁-C₆-alkoxycarbonyl-C₁-C₆-alkyl,        -   v) C₁-C₆-alkyl,        -   vi) carboxy-C₁-C₆-alkyl,        -   vii) C₃-C₈-cycloalkyl,        -   viii) C₃-C₈-cycloalkyl-C₁-C₆-alkyl,        -   ix) hydroxy-C₁-C₆-alkyl,        -   x) phenyl, and        -   xi) heteroaryl-C₁-C₆-alkyl;    -   R_(O) is selected from the group consisting of        -   i) H, and        -   ii) C₁-C₆-alkyl;    -   or R_(N) and R_(O) together with the nitrogen atom to which they        are attached form a heterocycloalkyl;    -   or pharmaceutically acceptable salts.

Another embodiment of the present invention provides compounds accordingto formula (I) as described herein, wherein R_(A) is selected from thegroup consisting of

-   -   i) C₁-C₆-alkyl,    -   ii) cyano-C₁-C₆-alkyl,    -   iii) C₃-C₈-cycloalkyl,    -   iv) aryl substituted with R_(G) and R_(G1),    -   v) heterocycloalkyl substituted with R_(G) and R_(G1), and    -   vi) heteroaryl substituted with R_(G) and R_(G1).

A particular embodiment of the present invention provides compoundsaccording to formula (I) as described herein, wherein R_(A) is selectedfrom the group consisting of

-   -   i) C₁-C₆-alkyl,    -   ii) cyano-C₁-C₆-alkyl,    -   iii) C₃-C₈-cycloalkyl,    -   iv) phenyl substituted with R_(G) and R_(G1),    -   v) tetrahydropyranyl substituted with R_(G) and R_(G1), and    -   vi) heteroaryl substituted with R_(G) and R_(G1), wherein        heteroaryl is selected from benzoxazolonyl, imidazolyl,        isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridinyl and        pyrimidinyl.

A more particular embodiment of the present invention provides compoundsaccording to formula (I) as described herein, wherein R_(A) is selectedfrom the group consisting of

-   -   i) C₁-C₆-alkyl,    -   ii) C₃-C₈-cycloalkyl,    -   iii) phenyl substituted with R_(G) and R_(G1), and    -   iv) heteroaryl substituted with R_(G) and R_(G1), wherein        heteroaryl is selected from isoxazolyl and pyridinyl.

A furthermore particular embodiment of the present invention providescompounds according to formula (I) as described herein, wherein R_(A) isselected from the group consisting of

-   -   i) C₁-C₆-alkyl, and    -   ii) phenyl substituted with R_(G) and R_(G1).

Another furthermore particular embodiment of the present inventionprovides compounds according to formula (I) as described herein, whereinR_(A) is C₁-C₆-alkyl.

Another furthermore particular embodiment of the present inventionprovides compounds according to formula (I) as described herein, whereinR_(A) is phenyl substituted with R and R_(G1).

Another embodiment of the present invention provides compounds accordingto formula (I) as described herein, wherein R_(G) is selected from thegroup consisting of

-   -   i) H,    -   ii) C₁-C₆-alkoxy,    -   iii) C₁-C₆-alkoxy-C₁-C₆-alkylcarbonylamino-C₁-C₆-alkyl,    -   iv)        C₁-C₆-alkoxy-C₁-C₆-alkylcarbonyl(C₁-C₆-alkyl)amino-C₁-C₆-alkyl,    -   v) C₁-C₆-alkoxycarbonyl,    -   vi) C₁-C₆-alkyl,    -   vii) C₁-C₆-alkylsulfonyl,    -   viii) carboxy,    -   ix) cyano,    -   x) C₃-C₈-cycloalkoxy,    -   xi) C₃-C₈-cycloalkylcarbonylamino-C₁-C₆-alkyl,    -   xii) C₃-C₈-cycloalkylcarbonyl(C₁-C₆-alkyl)amino-C₁-C₆-alkyl,    -   xiii) halo-C₁-C₆-alkyl,    -   xiv) halogen,    -   xv) hydroxy,    -   xvi) aminocarbonyl substituted on the nitrogen atom with R_(N)        and R_(O),    -   xvii) aminocarbonyl-C₁-C₆-alkoxy substituted on the nitrogen        atom with R_(N) and R_(O),    -   xviii) heteroaryl substituted with one H or C₁-C₆-alkyl,    -   xix) heterocycloalkyl-C₁-C₆-alkoxy substituted with one H or        C₁-C₆-alkyl, and    -   xx) heterocycloalkyl-C₁-C₆-alkyl substituted with one H or        C₁-C₆-alkyl.

Another embodiment of the present invention provides compounds accordingto formula (I) as described herein, wherein R_(G) is selected from thegroup consisting of

-   -   i) H,    -   ii) C₁-C₆-alkoxy,    -   iii) C₁-C₆-alkoxy-C₁-C₆-alkylcarbonylamino-C₁-C₆-alkyl,    -   iv)        C₁-C₆-alkoxy-C₁-C₆-alkylcarbonyl(C₁-C₆-alkyl)amino-C₁-C₆-alkyl,    -   v) C₁-C₆-alkoxycarbonyl,    -   vi) C₁-C₆-alkyl,    -   vii) C₁-C₆-alkylsulfonyl,    -   viii) carboxy,    -   ix) cyano,    -   x) C₃-C₈-cycloalkoxy,    -   xi) C₃-C₈-cycloalkylcarbonylamino-C₁-C₆-alkyl,    -   xii) C₃-C₈-cycloalkylcarbonyl(C₁-C₆-alkyl)amino-C₁-C₆-alkyl,    -   xiii) halo-C₁-C₆-alkyl,    -   xiv) halogen,    -   xv) aminocarbonyl substituted on the nitrogen atom with R_(N)        and R_(O),    -   xvi) aminocarbonyl-C₁-C₆-alkoxy substituted on the nitrogen atom        with R_(N) and R_(O).    -   xvii) heteroaryl substituted with one H or C₁-C₆-alkyl,    -   xviii) heterocycloalkyl-C₁-C₆-alkoxy substituted with one H or        C₁-C₆-alkyl, and    -   xix) heterocycloalkyl-C₁-C₆-alkyl substituted with one H or        C₁-C₆-alkyl.

A particular embodiment of the present invention provides compoundsaccording to formula (I) as described herein, wherein R_(G) is selectedfrom the group consisting of

-   -   i) H,    -   ii) C₁-C₆-alkoxy,    -   iii)        C₁-C₆-alkoxy-C₁-C₆-alkylcarbonyl(C₁-C₆-alkyl)amino-C₁-C₆-alkyl,    -   iv) C₃-C₈-cycloalkoxy,    -   v) halogen,    -   vi) hydroxy,    -   vii) aminocarbonyl substituted on the nitrogen atom with R_(N)        and R_(O),    -   viii) aminocarbonyl-C₁-C₆-alkoxy substituted on the nitrogen        atom with R_(N) and R_(O),    -   ix) heteroaryl substituted with one H or C₁-C₆-alkyl, and    -   x) heterocycloalkyl-C₁-C₆-alkyl substituted with one H or        C₁-C₆-alkyl.

Another particular embodiment of the present invention providescompounds according to formula (I) as described herein, wherein R_(G) isselected from the group consisting of

-   -   i) H,    -   ii) C₁-C₆-alkoxy,    -   iii)        C₁-C₆-alkoxy-C₁-C₆-alkylcarbonyl(C₁-C₆-alkyl)amino-C₁-C₆-alkyl,    -   iv) C₃-C₈-cycloalkoxy,    -   v) halogen,    -   vi) aminocarbonyl substituted on the nitrogen atom with R_(N)        and R_(O),    -   vii) aminocarbonyl-C₁-C₆-alkoxy substituted on the nitrogen atom        with R_(N) and R_(O),    -   viii) heteroaryl substituted with one H or C₁-C₆-alkyl, and    -   ix) heterocycloalkyl-C₁-C₆-alkyl substituted with one H or        C₁-C₆-alkyl.

Another embodiment of the present invention provides compounds accordingto formula (I) as described herein, wherein R_(G1) is selected from thegroup consisting of

-   -   i) H,    -   ii) halogen,    -   iii) C₁-C₆-alkyl, and    -   iv) halo-C₁-C₆-alkoxy.

A particular embodiment of the present invention provides compoundsaccording to formula (I) as described herein, wherein R_(C1) is selectedfrom the group consisting of

-   -   i) H, and    -   ii) halogen.

Another embodiment of the present invention provides compounds accordingto formula (I) as described herein, wherein R_(G2) is H.

Another embodiment of the present invention provides compounds accordingto formula (I) as described herein, wherein R_(L) and R_(M) are H.

Another embodiment of the present invention provides compounds accordingto formula (I) as described herein, wherein R_(N) is selected from thegroup consisting of

-   -   i) C₁-C₆-alkoxy-C₁-C₆-alkyl, and    -   ii) C₁-C₆-alkyl.

Another particular embodiment of the present invention providescompounds according to formula (I) as described herein, wherein R_(O) isC₁-C₆-alkyl.

Another particular embodiment of the present invention providescompounds according to formula (I) as described herein, wherein R_(N)and R_(O) together with the nitrogen atom to which they are attachedform morpholinyl, pyrrolidinyl or methylpiperazinonyl.

Another particular embodiment of the present invention providescompounds according to formula (I) as described herein, wherein R_(B) isselected from the group consisting of

-   -   i) C₁-C₆-alkyl,    -   ii) C₁-C₆-alkylsulfonyl,    -   iii) C₁-C₆-alkylsulfonylamino,    -   iv) aminocarbonyl,    -   v) cyano,    -   vi) halogen,    -   vii) heterocycloalkyl, wherein heteroaryl is selected from        oxadiazolyl, imidazolyl, 1,3,4-oxazolyl and 1,2,4-oxazolyl, and    -   viii) morpholinyl substituted with one H, C₁-C₆-alkyl or        trialkylsilyl-C₁-C₆-alkoxy-C₁-C₆-alkyl.

A more particular embodiment of the present invention provides compoundsaccording to formula (I) as described herein, wherein R_(B) is selectedfrom the group consisting of

-   -   i) cyano, and    -   ii) halogen.

A furthermore particular embodiment of the present invention providescompounds according to formula (I) as described herein, wherein R_(B) ishalogen.

Another particular embodiment of the present invention providescompounds according to formula (I) as described herein, wherein R_(C) isselected from the group consisting of

-   -   i) H,    -   ii) C₁-C₆-alkyl, and    -   iii) halogen.

A more particular embodiment of the present invention provides compoundsaccording to formula (I) as described herein, wherein R_(C) isC₁-C₆-alkyl.

Another particular embodiment of the present invention providescompounds according to formula (I) as described herein, wherein R_(C1)is H.

Another particular embodiment of the present invention providescompounds according to formula (I) as described herein, wherein W isselected from the ring systems A, B and C.

Another particular embodiment of the present invention providescompounds according to formula (I) as described herein, wherein W isselected from the ring systems A and C.

A more particular embodiment of the present invention provides compoundsaccording to formula (I) as described herein, wherein W is the ringsystem A.

Another particular embodiment of the present invention providescompounds according to formula (I) as described herein, wherein R_(G1)is C₁-C₆-alkyl.

Another particular embodiment of the present invention providescompounds according to formula (I) as described herein, wherein R_(D2)is selected from the group consisting of

-   -   i) H,    -   ii) halogen,    -   iii) hydroxy-C₁-C₆-alkoxy,    -   iv) hydroxy-C₁-C₆-alkyl(C₁-C₆-alkyl)amino,    -   v) hydroxy-C₁-C₆-alkylamino,    -   vi) dihydroxy-C₁-C₆-alkoxy,    -   vii) dihydroxy-C₁-C₆-alkyl(C₁-C₆-alkyl)amino, and    -   viii) heterocycloalkyl.

A more particular embodiment of the present invention provides compoundsaccording to formula (I) as described herein, wherein R_(D2) is selectedfrom the group consisting of

-   -   i) H,    -   ii) hydroxy-C₁-C₆-alkoxy, and    -   iii) hydroxy-C₁-C₆-alkyl(C₁-C₆-alkyl)amino.

Another particular embodiment of the present invention providescompounds according to formula (I) as described herein, wherein R_(D3)is selected from the group consisting of

-   -   i) H,    -   ii) C₁-C₆-alkoxy-C₁-C₆-alkylcarbonyl,    -   iii) C₁-C₆-alkoxycarbonyl, and    -   iv) C₁-C₆-alkylcarbonyl.

Another particular embodiment of the present invention providescompounds according to formula (I) as described herein, wherein R_(D4)is selected from the group consisting of

-   -   i) H,    -   ii) C₁-C₆-alkoxycarbonyl,    -   iii) heterocycloalkylcarbonyl, and    -   iv) aminocarbonyl substituted on the nitrogen atom with one to        two independently selected C₁-C₆-alkyl.

A particular embodiment of the present invention provides compoundsaccording to formula I(a) as described herein,

or pharmaceutically acceptable salts.

A further particular embodiment of the present invention providescompounds according to formula I(b) as described herein,

-   -   wherein    -   R_(A) is selected from the group consisting of        -   i) C₁-C₆-alkyl, and        -   ii) phenyl substituted with R_(G) and R_(G1);    -   R_(B) is selected from the group consisting of        -   i) cyano, and        -   ii) halogen;    -   R_(C) is selected from the group consisting of        -   i) H,        -   ii) C₁-C₆-alkyl, and        -   iii) halogen;    -   R_(D1) is C₁-C₆-alkyl;    -   R_(G) is selected from the group consisting of        -   i) H,        -   ii) C₁-C₆-alkoxy,        -   iii)            C₁-C₆-alkoxy-C₁-C₆-alkylcarbonyl(C₁-C₆-alkyl)amino-C₁-C₆-alkyl,        -   iv) halogen,        -   v) aminocarbonyl substituted on the nitrogen atom with R_(N)            and R_(O),        -   vi) aminocarbonyl-C₁-C₆-alkoxy substituted on the nitrogen            atom with R_(N) and R_(O),        -   vii) heteroaryl substituted with one H or C₁-C₆-alkyl,            wherein heteroaryl is isoxazolyl, oxazolyl or pyrazolyl, and        -   viii) heterocycloalkyl-C₁-C₆-alkoxy substituted with one H            or C₁-C₆-alkyl, wherein heterocycloalkyl-C₁-C₆-alkoxy is            tetrahydropyranylmethoxy or tetrahydrofuranylmethoxy;    -   R₂ is H and R_(G1) is selected from the group consisting of        -   i) H, and        -   ii) halogen;    -   R_(N) is selected from the group consisting of        -   i) C₁-C₆-alkoxy-C₁-C₆-alkyl, and        -   ii) C₁-C₆-alkyl;    -   R_(O) is C₁-C₆-alkyl;    -   or R_(N) and R_(O) together with the nitrogen atom to which they        are attached form morpholinyl, pyrrolidinyl or        methylpiperazinonyl;    -   or pharmaceutically acceptable salts.

A further particular embodiment of the present invention providescompounds according to formula I(b) as described herein,

-   -   wherein    -   R_(A) is selected from the group consisting of        -   i) C₁-C₆-alkyl, and        -   ii) phenyl substituted with R_(G) and R_(G1);    -   R_(B) is selected from the group consisting of        -   i) cyano, and        -   ii) halogen;    -   R_(D1) is C₁-C₆-alkyl;    -   R_(G) is selected from the group consisting of        -   i) H,        -   ii) C₁-C₆-alkoxy,        -   iii) C₁-C₆-alkoxy-C₁-C₆-alkylcarbonylamino-C₁-C₆-alkyl,        -   iv)            C₁-C₆-alkoxy-C₁-C₆-alkylcarbonyl(C₁-C₆-alkyl)amino-C₁-C₆-alkyl,        -   v) C₁-C₆-alkoxycarbonyl,        -   vi) C₁-C₆-alkyl,        -   vii) C₁-C₆-alkylsulfonyl,        -   viii) carboxy,        -   ix) cyano,        -   x) C₃-C₈-cycloalkoxy,        -   xi) C₃-C₈-cycloalkylcarbonylamino-C₁-C₆-alkyl,        -   xii) C₃-C₈-cycloalkylcarbonyl(C₁-C₆-alkyl)amino-C₁-C₆-alkyl,        -   xiii) halo-C₁-C₆-alkyl,        -   xiv) halogen,        -   xv) aminocarbonyl substituted on the nitrogen atom with            R_(N) and R_(O),        -   xvi) aminocarbonyl-C₁-C₆-alkoxy substituted on the nitrogen            atom with R_(N) and R_(O),        -   xvii) heteroaryl substituted with one H, C₁-C₆-alkyl,            wherein heteroaryl is isoxazolyl, oxazolyl or pyrazolyl,        -   xviii) heterocycloalkyl-C₁-C₆-alkoxy substituted with one H,            C₁-C₆-alkyl, wherein heterocycloalkyl-C₁-C₆-alkoxy is            tetrahydropyranylmethoxy or tetrahydrofuranylmethoxy, and        -   xix) heterocycloalkyl-C₁-C₆-alkyl substituted with one H,            C₁-C₆-alkyl, wherein heterocycloalkyl-C₁-C₆-alkyl is            methyldioxopiperazinylmethyl, oxopyrrolidinylmethyl or            oxooxazolidinylmethyl;    -   R_(G2) is H and R_(G1) is selected from the group consisting of        -   i) H,        -   ii) halogen,        -   iii) C₁-C₆-alkyl,        -   iv) halo-C₁-C₆-alkoxy, and    -   R_(N) is selected from the group consisting of        -   i) H,        -   ii) C₁-C₆-alkoxy,        -   iii) C₁-C₆-alkoxy-C₁-C₆-alkyl,        -   iv) C₁-C₆-alkoxycarbonyl-C₁-C₆-alkyl,        -   v) C₁-C₆-alkyl,        -   vi) carboxy-C₁-C₆-alkyl,        -   vii) C₃-C₈-cycloalkyl,        -   viii) C₃-C₈-cycloalkyl-C₁-C₆-alkyl,        -   ix) hydroxy-C₁-C₆-alkyl,        -   x) phenyl, and        -   xi) heteroaryl-C₁-C₆-alkyl, wherein heteroaryl-C₁-C₆-alkyl            is are pyridinylalkyl or thiophenylalkyl;    -   R_(O) is selected from the group consisting of        -   i) H, and        -   ii) C₁-C₆-alkyl;    -   or R_(N) and R_(O) together with the nitrogen atom to which they        are attached form piperidinyl, morpholinyl, pyrrolidinyl or        methylpiperazinonyl;    -   or pharmaceutically acceptable salts.

A furthermore particular embodiment of the present invention providescompounds according to formula I(b) as described herein,

-   -   wherein    -   R_(A) is C₁-C₆-alkyl;    -   R_(C) is selected from the group consisting of        -   i) C₁-C₆-alkyl, and        -   ii) halogen;    -   R_(D1) is C₁₋₆-alkyl;    -   or pharmaceutically acceptable salts.

Particular examples of compounds of formula (I) as described herein areselected from

-   3-[(2-tert-butyl-4-chloro-5-methylphenoxy)methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   3-[(2-tert-butyl-4-chloro-5-fluorophenoxy)methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   3-[(3,3-dimethyl-6-propan-2-yl-1,2-dihydroinden-5-yl)oxymethyl]-4-methyl-1H-1,2,4-triazol-5-one;-   3-[[2-tert-butyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   3-[[2-tert-butyl-4-[1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   3-[[2-tert-butyl-4-(1-methylimidazol-2-yl)phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   3-[[2-tert-butyl-4-(1,3-oxazol-2-yl)phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   3-[(2-tert-butyl-4-morpholin-4-yl)phenoxy)methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   3-[[2-tert-butyl-4-(3-methylimidazol-4-yl)phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   3-[[2-tert-butyl-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]-3-propan-2-ylbenzonitrile;-   2-methyl-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]-5-propan-2-ylbenzonitrile;-   3-tert-butyl-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile;-   3-[(4-chloro-2-cyclopropyl-5-methylsulfonylphenoxy)methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   3-[(2-tert-butyl-4-methylsulfonylphenoxy)methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   5-tert-butyl-2-methyl-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile;-   4-tert-butyl-2-methyl-5-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile;-   3-[[2-tert-butyl-4-[3-(2-trimethylsilyl-ethoxymethyl)imidazol-4-yl]phenoxy]-methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   3-[(4-chloro-2-cyclopropyl-5-methylphenoxy)methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   3-[(4-chloro-2-cyclohexyl-5-methylphenoxy)methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   3-[[4-chloro-5-methyl-2-(oxan-4-yl)phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   2-chloro-4-cyclopropyl-5-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile;-   N-[2-chloro-4-cyclopropyl-5-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]methanesulfonamide;-   4-tert-butyl-3-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile;-   4-tert-butyl-3-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxybenzamide;-   5-tert-butyl-2-methyl-4-[(5-oxo-4-propan-2-yl-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile;-   4-methyl-3-[(5-methyl-2-propan-2-ylphenoxy)methyl]-1H-1,2,4-triazol-5-one;-   3-[(4-chloro-5-methyl-2-propan-2-ylphenoxy)methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   3-[(4-chloro-2-propan-2-ylphenoxy)methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   3-(6-cyclopropyl-2-methyl-1,3-benzothiazol-5-yl)oxymethyl]-4-methyl-1H-1,2,4-triazol-5-one;-   3-[(4-chloro-2-cyclobutyl-5-methylphenoxy)methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   3-[[2-tert-butyl-4-(1H-imidazol-2-yl)phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   3-[[2-tert-butyl-4-(1H-imidazol-5-yl)phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   3-[(4-chloro-5-methyl-2-phenylphenoxy)methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   3-[[4-chloro-2-(2-chlorophenyl)-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   3-[[4-chloro-2-(3-chlorophenyl)-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   3-[[4-chloro-2-(4-chlorophenyl)-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]benzonitrile;-   3-[[4-chloro-5-methyl-2-(3-methylsulfonylphenyl)phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   3-[[4-chloro-5-methyl-2-(2-methylsulfonylphenyl)phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   3-[[4-chloro-5-methyl-2-[3-(piperidine-1-carbonyl)phenyl]phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-N-cyclohexylbenzamide;-   3-[[4-chloro-5-methyl-2-[3-(morpholine-4-carbonyl)phenyl]phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]benzamide;-   3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-N,N-dimethylbenzamide;-   3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-N-phenylbenzamide;-   3-chloro-5-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]benzamide;-   3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-N-cyclopropyl-4-fluorobenzamide;-   4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy-3-phenylbenzonitrile;-   3-[5-chloro-4-methyl-2-(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-N-(2-methoxyethyl)benzamide;-   3-[[4-chloro-2-(2-chloropyridin-3-yl)-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   3-[[4-chloro-2-(6-chloropyridin-2-yl)-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   5-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]pyridine-3-carboxamide;-   3-[[4-chloro-2-(6-methoxypyridin-2-yl)-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   3-[(4-chloro-5-methyl-2-pyrazin-2-ylphenoxy)methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   3-[(4-chloro-5-methyl-2-pyrimidin-2-ylphenoxy)methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   3-[[4-chloro-5-methyl-2-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   3-[[4-chloro-5-methyl-2-(1,2-oxazol-5-yl)phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   3-[[4-chloro-5-methyl-2-(1,3-oxazol-5-yl)phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   3-[[4-chloro-5-methyl-2-(3-methylimidazol-4-yl)phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   3-[[4-chloro-2-(1H-imidazol-5-yl)-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   3-[[4-chloro-5-methyl-2-(1,3-oxazol-2-yl)phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   3-[[4-chloro-5-methyl-2-(2-methylpyrazol-3-yl)phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   2-chloro-4-(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy-5-phenylbenzonitrile;-   2-chloro-5-(4-fluorophenyl)-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile;-   3-[4-chloro-5-cyano-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-N-methylbenzamide,-   2-chloro-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]-5-[3-(1H-pyrazol-3-yl)phenyl]benzonitrile;-   2-chloro-5-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile;-   3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-N-(2-hydroxyethyl)benzamide;-   2-chloro-5-[3-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl]-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile;-   3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-4-fluoro-N,N-dimethylbenzamide;-   3-[4-chloro-5-cyano-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-N,N-dimethylbenzamide;-   3-[[4-chloro-2-[2-fluoro-5-(morpholine-4-carbonyl)phenyl]-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   2-chloro-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]-5-[3-(morpholine-4-carbonyl)phenyl]benzonitrile;-   methyl    3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]benzoate;-   3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]benzoic    acid;-   methyl    3-[[3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,24-triazol-3-yl)methoxy]phenyl]benzoyl]amino]propanoate;-   3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-N-(2-hydroxyethyl)-N-methylbenzamide;-   ethyl    2-[[3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]benzoyl]amino]acetate;-   3-[[3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]benzoyl]amino]propanoic    acid;-   2-[[3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]benzoyl]amino]acetic    acid;-   methyl    3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-4-methylbenzoate;-   3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-4-methylbenzoic    acid;-   3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-N,N,4-trimethylbenzamide;-   3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-4-(trifluoromethoxy)benzamide;-   3-[[4-chloro-2-(2-methoxypyridin-3-yl)-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   2-chloro-5-(2-methoxypyridin-3-yl)-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile;-   3-[[4-chloro-2-(5-ethoxy-2-fluorophenyl)-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   3-[[4-chloro-2-(2-methoxyphenyl)-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   3-[[4-chloro-2-(2-fluoro-5-propan-2-yloxyphenyl)-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   3-[[4-chloro-2-[2-fluoro-5-(2-methylpropoxy)phenyl]-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   3-[[4-chloro-2-[2-methoxy-5-(trifluoromethyl)phenyl]-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   3-[[4-chloro-2-(2-methoxy-5-propan-2-ylphenyl)-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   2-chloro-5-[2-fluoro-5-(morpholine-4-carbonyl)phenyl]-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile;-   3-[[4-chloro-2-[2-fluoro-5-(pyrrolidine-1-carbonyl)phenyl]-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-N-cyclopropyl-4-fluoro-N-methylbenzamide;-   3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-4-fluoro-N-(2-hydroxyethyl)-N-methylbenzamide;-   4-[3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-4-fluorobenzoyl]-1-methylpiperazin-2-one;-   3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-N-cyclopentyl-4-fluoro-N-methylbenzamide;-   3-[[4-chloro-2-[2-fluoro-5-(oxolan-3-ylmethoxy)phenyl]-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-4-fluoro-N-methyl-N-(thiophen-2-ylmethyl)benzamide;-   3-[[4-chloro-2-[2-fluoro-5-(piperidine-1-carbonyl)phenyl]-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-N-(cyclopropylmethyl)-4-fluoro-N-methylbenzamide;-   3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-4-fluoro-N-methyl-N-(pyridin-2-ylmethyl)benzamide;-   3-[[4-chloro-2-[2-fluoro-5-(oxan-4-ylmethoxy)phenyl]-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-4-fluoro-N-(2-methoxyethyl)-N-methylbenzamide;-   3-[[4-chloro-2-[2-fluoro-5-(oxolan-2-ylmethoxy)phenyl]-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   2-[3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-4-fluorophenoxy]-N,N-dimethylacetamide;-   1-[[3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-4-fluorophenyl]methyl]-4-methylpiperazine-2,5-dione;-   7-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-6-fluoro-3-methyl-1,3-benzoxazol-2-one;-   N-[[3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-4-fluorophenyl]methyl]-2-methoxy-N-methylacetamide;-   N-[[3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-4-fluorophenyl]methyl]cyclopropanecarboxamide;-   N-[[3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-4-fluorophenyl]methyl]-N-methylcyclopropanecarboxamide;-   3-[[4-chloro-2-[2-fluoro-5-[(2-oxopyrrolidin-1-yl)methyl]phenyl]-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   3-[[3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-4-fluorophenyl]methyl]-1,3-oxazolidin-2-one;-   N-[[3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-4-fluorophenyl]methyl]-2-methoxyacetamide;-   2-chloro-5-(2-fluorophenyl)-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile;-   2-chloro-5-(3-fluorophenyl)-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile;-   3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-4-(trifluoromethoxy)benzonitrile;-   2-chloro-5-[2-fluoro-5-(oxolan-2-ylmethoxy)phenyl]-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile;-   2-chloro-5-(2-fluoro-3-methoxyphenyl)-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile;-   2-chloro-5-(2-fluoro-5-propan-2-yloxyphenyl)-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile;-   3-[[4-chloro-2-(2-fluoro-3-methoxyphenyl)-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   2-chloro-5-(2,3-difluorophenyl)-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile;-   3-[[4-chloro-2-(5-cyclopropyloxy-2-fluorophenyl)-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   2-chloro-5-(5-chloro-2-fluorophenyl)-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile;-   2-chloro-5-(2,5-difluorophenyl)-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile;-   2-chloro-5-(5-cyclopropyloxy-2-fluorophenyl)-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile;-   2-chloro-5-[2-fluoro-5-(trifluoromethyl)phenyl]-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile;-   3-[(4-chloro-5-methyl-2-propan-2-ylphenoxy)methyl]-1H-pyridazin-6-one;-   3-[(4-chloro-2-cyclopropyl-5-methylphenoxy)methyl]-1H-pyridazin-6-one;-   3-[(4-chloro-5-fluoro-2-propan-2-ylphenoxy)methyl]-1H-pyridazin-6-one;-   3-[(5-chloro-4-methyl-2-propan-2-ylphenoxy)methyl]-1H-pyridazin-6-one;-   3-[(4-chloro-2-cyclobutyl-5-methylphenoxy)methyl]-1H-pyridazin-6-one;-   3-[(4-chloro-2-cyclohexyl-5-methylphenoxy)methyl]-1H-pyridazin-6-one;-   3-[[4-chloro-5-methyl-2-(oxan-4-yl)phenoxy]methyl]-1H-pyridazin-6-one;-   3-[(2-tert-butyl-4-chloro-5-methylphenoxy)methyl]-1H-pyridazin-6-one;-   2-[5-chloro-4-methyl-2-[(6-oxo-1H-pyridazin-3-yl)methoxy]phenyl]-2-methylpropanenitrile;-   3-[(2-tert-butyl-4-methylsulfonylphenoxy)methyl]-1H-indazole;-   3-[(4-chloro-5-methyl-2-propan-2-ylphenoxy)methyl]-1H-indazole;-   3-[(2-tert-butyl-4-chloro-5-methylphenoxy)methyl]-1H-pyrazolo[3,4-b]pyridine;-   5-tert-butyl-2-methyl-4-(1H-pyrazolo[3,4-b]pyridin-3-ylmethoxy)benzonitrile;-   5-[5-chloro-4-methyl-2-(1H-pyrazolo[3,4-b]pyridin-3-ylmethoxy)phenyl]-1,2-oxazole-   3-[(2-tert-butyl-4-chloro-5-methylphenoxy)methyl]-6-fluoro-1H-pyrazolo[3,4-b]pyridine;-   2-[[3-[(2-tert-butyl-4-chloro-5-methylphenoxy)methyl]-1H-pyrazolo[3,4-b]pyridin-6-yl]amino]ethanol;-   2-[[3-[(2-tert-butyl-4-chloro-5-methylphenoxy)methyl]-1H-pyrazolo[3,4-b]pyridin-6-yl]-methylamino]ethanol;-   3-[(2-tert-butyl-5-methyl-4-methylsulfonylphenoxy)methyl]-1H-pyrazolo[3,4-b]pyridine;-   3-[(2-tert-butyl-5-methyl-4-methylsulfonylphenoxy)methyl]-1H-indazole;-   2-[[3-[(2-tert-butyl-4-chloro-5-fluorophenoxy)methyl]-1H-pyrazolo[3,4-b]pyridin-6-yl]amino]ethanol;-   3-[(2-tert-butyl-4-chloro-5-fluorophenoxy)methyl]-6-fluoro-1H-pyrazolo[3,4-b]pyridine-   2-[[3-[(2-tert-butyl-4-chloro-5-methylphenoxy)methyl]-1H-pyrazolo[3,4-b]pyridin-6-yl]oxy]ethanol;-   2-[[3-[(2-tert-butyl-4-chloro-5-fluorophenoxy)methyl]-1H-pyrazolo[3,4-b]pyridin-6-yl]-methylamino]ethanol;-   3-[[3-[(2-tert-butyl-4-chloro-5-methylphenoxy)methyl]-1H-pyrazolo[3,4-b]pyridin-6-yl]oxy]propane-1,2-diol;-   3-[5-chloro-4-methyl-2-(1H-pyrazolo[3,4-b]pyridin-3-ylmethoxy)phenyl]-N-(2-methoxyethyl)benzamide;-   [3-[5-chloro-4-methyl-2-(1H-pyrazolo[3,4-b]pyridin-3-ylmethoxy)phenyl]phenyl]-morpholin-4-ylmethanone;-   3-[5-chloro-4-methyl-2-(1H-pyrazolo[3,4-b]pyridin-3-ylmethoxy)phenyl]-N,N-dimethylbenzamide;-   3-[5-chloro-4-methyl-2-(1H-pyrazolo[3,4-b]pyridin-3-ylmethoxy)phenyl]-N-(2-hydroxyethyl)benzamide;-   3-[[4-chloro-2-(2-methoxypyridin-3-yl)-5-methylphenoxy]methyl]-1H-pyrazolo[3,4-b]pyridine;-   3-[5-chloro-4-methyl-2-(1H-pyrazolo[3,4-b]pyridin-3-ylmethoxy)phenyl]-4-fluoro-N,N-dimethylbenzamide;-   [3-[5-chloro-4-methyl-2-(1H-pyrazolo[3,4-b]pyridin-3-ylmethoxy)phenyl]-4-fluorophenyl]-morpholin-4-ylmethanone;-   3-[(2-tert-butyl-4-chloro-5-methylphenoxy)methyl]-1H-pyrazolo[4,3-b]pyridine;-   3-[5-chloro-4-methyl-2-(1H-pyrazolo[4,3-b]pyridin-3-ylmethoxy)phenyl]-N,N-dimethylbenzamide;-   3-[(2-tert-butyl-4-chloro-5-fluorophenoxy)methy]-1H-pyrazolo[4,3-b]pyridine;-   2-[[3-[(2-tert-butyl-4-chloro-5-methylphenoxy)methyl]-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-methylamino]ethanol;-   3-[[3-[(2-tert-butyl-4-chloro-5-methylphenoxy)methyl]-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-methylamino]propane-1,2-diol;-   3-[5-chloro-4-methyl-2-(1H-pyrazolo[4,3-b]pyridin-3-ylmethoxy)phenyl]-4-fluoro-N,N-dimethylbenzamide;-   1-[3-[(2-tert-butyl-4-chloro-5-methylphenoxy)methyl]-1H-pyrazolo[3,4-d]pyrimidin-6-yl]azetidin-3-ol;-   2-[[3-[(2-tert-butyl-4-chloro-5-methylphenoxy)methyl]-1H-pyrazolo[3,4-d]pyrimidin-6-yl]amino]ethanol;-   2-[[3-[(2-tert-butyl-4-chloro-5-methylphenoxy)methyl]-1H-pyrazolo[3,4-d]pyrimidin-6-yl]oxy]ethanol;-   5-tert-butyl-4-[[6-(3-hydroxyazetidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]methoxy]-2-methylbenzonitrile;-   5-tert-butyl-4-[[6-[2-hydroxyethyl(methyl)amino]-1H-pyrazolo[3,4-d]pyrimidin-3-yl]methoxy]-2-methylbenzonitrile;-   3-[[3-[(2-tert-butyl-4-chloro-5-methylphenoxy)methyl]-1H-pyrazolo[3,4-d]pyrimidin-6-yl]oxy]propane-1,2-diol;-   5-tert-butyl-4-[[6-(2-hydroxyethylamino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]methoxy]-2-methylbenzonitrile;-   5-tert-butyl-4-[[6-[2,3-dihydroxypropyl(methyl)amino]-1H-pyrazolo[3,4-d]pyrimidin-3-yl]methoxy]-2-methylbenzonitrile;-   5-tert-butyl-4-[[6-(2,3-dihydroxypropoxy)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]methoxy]-2-methylbenzonitrile;-   5-tert-butyl-4-[[6-(2-hydroxyethoxy)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]methoxy]-2-methylbenzonitrile;-   4-[3-[5-chloro-4-methyl-2-(1H-pyrazolo[3,4-b]pyridin-3-ylmethoxy)phenyl]-4-fluorobenzoyl]-1-methylpiperazin-2-one;-   3-[5-chloro-4-methyl-2-(1H-pyrazolo[3,4-b]pyridin-3-ylmethoxy)phenyl]-4-fluoro-N-(2-methoxyethyl)-N-methylbenzamide;-   4-[3-[5-chloro-2-(1H-indazol-3-ylmethoxy)-4-methylphenyl]-4-fluorobenzoyl]-1-methylpiperazin-2-one;-   [3-[5-chloro-4-methyl-2-(1H-pyrazolo[3,4-b]pyridin-3-ylmethoxy)phenyl]-4-fluorophenyl]-pyrrolidin-1-ylmethanone;-   2-chloro-5-[2-fluoro-5-(pyrrolidine-1-carbonyl)phenyl]-4-(1H-pyrazolo[3,4-b]pyridin-3-ylmethoxy)benzonitrile;-   4-[3-[5-chloro-4-methyl-2-(H-pyrazolo[3,4-c]pyridin-3-ylmethoxy)phenyl]-4-fluorobenzoyl]-1-methylpiperazin-2-one;-   3-[(2-tert-butyl-4-methylsulfonylphenoxy)methyl]-1H-pyrazolo[3,4-b]pyridine;-   3-[5-chloro-4-methyl-2-(1H-pyrazolo[3,4-c]pyridin-3-ylmethoxy)phenyl]-4-fluoro-N-(2-methoxyethyl)-N-methylbenzamide;-   3-[[4-chloro-2-(2-methoxypyridin-3-yl)-5-methylphenoxy]methyl]-1H-pyrazolo[3,4-c]pyridine;-   4-tert-butyl-2-methyl-5-(1H-pyrazolo[3,4-b]pyridin-3-ylmethoxy)benzonitrile;-   4-tert-butyl-2-methyl-5-(1H-pyrazolo[3,4-c]pyridin-3-ylmethoxy)benzonitrile;-   tert-butyl    3-((2-tert-butyl-4-chloro-5-methylphenoxy)methyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate;-   1-(3-((2-tert-butyl-4-chloro-5-methylphenoxy)methyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone;-   1-(3-((2-tert-butyl-4-chloro-5-methylphenoxy)methyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)-2-methoxyethanone;-   3-((2-tert-butyl-4-chloro-5-methylphenoxy)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine;-   1-(3-((2-tert-butyl-4-chloro-5-methylphenoxy)methyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)ethanone;-   1-(3-((2-tert-butyl-4-chloro-5-methylphenoxy)methyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)-2-methoxyethanone;-   3-((4-chloro-2-(2-methoxypyridin-3-yl)-5-methylphenoxy)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine;-   1-(3-((4-chloro-2-(2-methoxypyridin-3-yl)-5-methylphenoxy)methyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)ethanone;-   3-((2-tert-butyl-4-chloro-5-methylphenoxy)methyl)-1H-pyrazole;-   4-((1H-pyrazol-3-yl)methoxy)-5-tert-butyl-2-methylbenzonitrile;-   methyl    3-((2-(tert-butyl)-4-chloro-5-methylphenoxy)methyl)-1H-pyrazole-5-carboxylate;-   (3-((2-(tert-butyl)-4-chloro-5-methylphenoxy)methyl)-1H-pyrazol-5-yl)(pyrrolidin-1-yl)methanone;-   3-((2-(tert-butyl)-4-chloro-5-methylphenoxy)methyl)-N,N-dimethyl-1H-pyrazole-5-carboxamide;-   and pharmaceutically acceptable salts thereof.-   Also particular examples of compounds of formula (I) as described    herein are selected from-   4-tert-butyl-2-chloro-5-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile;-   2-chloro-5-[2-fluoro-5-(trifluoromethoxy)phenyl]-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile;-   2-chloro-5-[2-fluoro-5-(2,2,2-trifluoroethoxy)phenyl]-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile;-   3-[[4-chloro-2-(2-methoxypyridin-3-yl)-5-methylphenoxy]methyl]-1H-pyridazin-6-one;-   3-[[4-chloro-2-(2-hydroxypyridin-3-yl)-5-methylphenoxy]methyl]-1H-pyridazin-6-one;-   2-chloro-4-[(6-oxo-1H-pyridazin-3-yl)methoxy]-5-phenylbenzonitrile-   4-tert-butyl-2-methyl-5-[(6-oxo-1H-pyridazin-3-yl)methoxy]benzonitrile;-   2-chloro-5-(5-cyclopropyloxy-2-fluorophenyl)-4-[(6-oxo-1H-pyridazin-3-yl)methoxy]benzonitrile;-   4-tert-butyl-2-chloro-5-(1H-pyrazolo[3,4-c]pyridin-3-ylmethoxy)benzonitrile-   2-chloro-5-(5-cyclopropyloxy-2-fluorophenyl)-4-(1H-pyrazolo[3,4-c]pyridin-3-ylmethoxy)benzonitrile;-   4-tert-butyl-2-chloro-5-(1H-pyrazolo[3,4-b]pyridin-3-ylmethoxy)benzonitrile-   2-chloro-5-(5-cyclopropyloxy-2-fluorophenyl)-4-(1H-pyrazolo[3,4-b]pyridin-3-ylmethoxy)benzonitrile;-   2-chloro-5-[2-fluoro-5-(trifluoromethoxy)phenyl]-4-(1H-pyrazolo[4,3-c]pyridin-3-ylmethoxy)benzonitrile;-   2-chloro-5-[2-fluoro-5-(trifluoromethoxy)phenyl]-4-(1H-pyrazolo[3,4-b]pyridin-3-ylmethoxy)benzonitrile;

and pharmaceutically acceptable salts thereof.

Further particular examples of compounds of formula (I) as describedherein are selected from

-   3-[(2-tert-butyl-4-chloro-5-methylphenoxy)methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   3-[(2-tert-butyl-4-chloro-5-fluorophenoxy)methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   3-tert-butyl-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile;-   5-tert-butyl-2-methyl-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile;-   4-tert-butyl-2-methyl-5-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile;-   3-[(4-chloro-2-cyclohexyl-5-methylphenoxy)methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   5-tert-butyl-2-methyl-4-[(5-oxo-4-propan-2-yl-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile;-   3-[(4-chloro-5-methyl-2-propan-2-ylphenoxy)methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   3-[(4-chloro-2-cyclobutyl-5-methylphenoxy)methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   3-[[4-chloro-5-methyl-2-[3-(morpholine-4-carbonyl)phenyl]phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   3-[[4-chloro-5-methyl-2-(1,2-oxazol-5-yl)phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   2-chloro-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]-5-phenylbenzonitrile;-   2-chloro-4-(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy-5-[3-(1H-pyrazol-3-yl)phenyl]benzonitrile;-   2-chloro-5-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile;-   3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-4-fluoro-N,N-dimethylbenzamide;-   3-[[4-chloro-2-(2-methoxypyridin-3-yl)-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   3-[[4-chloro-2-(2-fluoro-5-propan-2-yloxyphenyl)-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   3-[[4-chloro-2-[2-fluoro-5-(pyrrolidine-1-carbonyl)phenyl]-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   4-[3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-4-fluorobenzoyl]-1-methylpiperazin-2-one;-   3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-4-fluoro-N-(2-methoxyethyl)-N-methylbenzamide;-   3-[[4-chloro-2-[2-fluoro-5-(oxolan-2-ylmethoxy)phenyl]-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   2-[3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-4-fluorophenoxy]-N,N-dimethylacetamide;-   N-[[3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-4-fluorophenyl]methyl]-2-methoxy-N-methylacetamide;-   2-chloro-5-(2-fluorophenyl)-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile;-   2-chloro-5-(2-fluoro-3-methoxyphenyl)-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile;-   2-chloro-5-(2-fluoro-5-propan-2-yloxyphenyl)-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile;-   3-[[4-chloro-2-(5-cyclopropyloxy-2-fluorophenyl)-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;-   2-chloro-5-(5-cyclopropyloxy-2-fluorophenyl)-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile;-   5-tert-butyl-2-methyl-4-(1H-pyrazolo[3,4-b]pyridin-3-ylmethoxy)benzonitrile;-   2-[[3-[(2-tert-butyl-4-chloro-5-methylphenoxy)methyl]-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-methylamino]ethanol;-   2-[[3-[(2-tert-butyl-4-chloro-5-methylphenoxy)methyl]-1H-pyrazolo[3,4-d]pyrimidin-6-yl]oxy]ethanol;-   2-chloro-5-[2-fluoro-5-(pyrrolidine-1-carbonyl)phenyl]-4-(1H-pyrazolo[3,4-b]pyridin-3-ylmethoxy)benzonitrile;-   3-[5-chloro-4-methyl-2-(1H-pyrazolo[3,4-c]pyridin-3-ylmethoxy)phenyl]-4-fluoro-N-(2-methoxyethyl)-N-methylbenzamide;-   and pharmaceutically acceptable salts thereof.-   Also further particular examples of compounds of formula (I) as    described herein are selected from-   2-chloro-5-(5-cyclopropyloxy-2-fluorophenyl)-4-[(6-oxo-1H-pyridazin-3-yl)methoxy]benzonitrile;-   4-tert-butyl-2-chloro-5-(1H-pyrazolo[3,4-b]pyridin-3-ylmethoxy)benzonitrile;

and pharmaceutically acceptable salts thereof.

Also particular examples of compounds of formula (I) as described hereinare selected from

-   4-[(2-tert-Butyl-4-chloro-5-methylphenoxy)methyl]-2H-triazole;-   3-[(2-tert-Butyl-4-chloro-5-methylphenoxy)methyl]-5-phenyl-1H-pyrazole;    and-   5-tert-Butyl-2-methyl-4-[(5-phenyl-1H-pyrazol-3-yl)methoxy]benzonitrile.

Further particular examples of compounds of formula (I) as describedherein are selected from

-   5-tert-butyl-2-methyl-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile;-   5-tert-butyl-2-chloro-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile;    and-   5-tert-butyl-2-fluoro-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile;

and pharmaceutically acceptable salts thereof.

Processes for the manufacture of compounds of formula (I) as describedherein are an object of the invention.

The preparation of compounds of formula (I) of the present invention maybe carried out in sequential or convergent synthetic routes. Synthesesof the invention are shown in the following general schemes. The skillsrequired for carrying out the reactions and purifications of theresulting products are known to those persons skilled in the art. Incase a mixture of enantiomers or diastereoisomers is produced during areaction, these enantiomers or diastereoisomers can be separated bymethods described herein or known to the man skilled in the art such ase.g. (chiral) chromatography or crystallization. The substituents andindices used in the following description of the processes have thesignificance given herein.

A general description of the invention is given in the followingsections. To obtain compounds of formula (I), either in an unprotectedor protected fashion (PG=protecting group), the key step is usually acoupling reaction between a suitable phenol building block A1, whereR_(A) is the mandatory ortho substituent to the aryl-hydroxy group,R_(B) is a substituent in another position of the phenyl ring thatusually needs to be introduced or modified (involving suitableprotection if there are any potentially interfering functional groupswithin R_(A) and R_(B)), and R_(C) is any other functional group that isusually present in the starting materials and remains unchanged, withthe desired building block A2 to provide a substituted phenylether offormula A3 (Scheme 1). Within the context of this invention, A2 usuallyconsists of a 5 or 6-membered heterocycle containing two adjacentnitrogen atoms, one of which is bearing a hydrogen (or a suitableprotecting group PG if the nitrogen is kept protected), and a methylgroup that is substituted by a suitable leaving group X. X can behalogen such as for example chloro, bromo or iodo or any other suitableleaving group such as tosylate or mesylate. A2 can also be bicyclic,where a 6 membered ring that is either aromatic or saturated and thatmay contain more nitrogen atoms and additional substituents is fused tothe primary 5-membered heterocycle. The coupling reaction between A1 andA2, which can both carry orthogonal protecting groups PG, PG′, or PG″ ifneeded, is usually carried out in the presence of a base such aspotassium carbonate, cesium carbonate or sodium hydride an appropriatesolvent such as THF. DMF, CH₃CN or similar at temperatures ranging fromminus 20° C. to the boiling point of the solvent or at even highertemperatures in sealed vessels to provide coupling product A3a. In manycases, if protection was not required, A3a is equal to A3 and is alreadyan example of a structure of formula (I), however, if A3a contains anyprotecting groups PG or PG′ or PG″ such as for example BOC or trityl,tert-butyl, pMB, MOM, SEM, benzyl or similar, they can be removed underknown conditions which are depending on the nature of the protectinggroup PG. BOC, tert-butyl, pMB and trityl, MOM, SEM for example, can beremoved in the presence of an acid such as TFA, HCl, HBr, H₂SO₄ orsimilar in a suitable solvent such as CH₂Cl₂, THF, water, dioxane orsimilar, whereas benzyl or similar can be removed by catalytichydrogenation (e.g. H₂, Pd on carbon or similar, in ethanol, methanolwater, EtOAc or HOAc or the like, at various temperatures). SEM can alsobe removed by fluoride treatment (e.g. tetrabutylammonium fluoride in,HMPT or DMPU or similar). Protecting group strategies for manyfunctional groups (including conditions for protection and deprotection)are well described for example in “Protective Groups in OrganicChemistry” by T. W. Greene and P. G. M. Wutts, 5th Ed., 2014, John Wiley& Sons, N.Y. Deprotection of A3a, if required, which can compriseseveral steps if PG, PG′ or PG″ are orthogonal, will provide thede-protected compound of formula A3 which corresponds to the compoundsof formula (I) as outlined in the claims.

Subsequent Modifications of Coupling Products

In some cases, depending on the nature of the building block A2 used forthe coupling reaction, the coupling product is not yet the desiredmaterial and further modifications which are distinct from simpleprotecting group manipulations are required to produce a compound offormula A3 (Scheme 2).

For Triazolones: If, for example, a commercial triazole building blocksuch as A4 with R_(D1)=methyl is used as A2 in the coupling reactionwith phenol A1, which is done under conditions which are describedabove, then suitable downstream transformations of the intermediatecoupling product A5 include: 1) the treatment of A5 with sodiummethoxide in a solvent such as methanol at temperatures ranging from 0°C. to the reflux temperature of the solvent to provide heteroaryl-methylether A6, and 2) the hydrolysis of A6 in the presence of a strong acidsuch as HCl. HBr, H₂SO₄ or p-toluenesulfonic acid or similar in solventssuch as acetic acid containing some water at temperatures ranging from0° C. to 130° C. to provide triazolones of formula A7, which are asubset of the compounds of formula A3 shown in Scheme 1.

For Pyridazinones: If, for example, a commercial pyridazinon buildingblock such as A8 is used in the coupling reaction with phenol A1, thenthe subsequent transformations that are needed to produce pyridazinonesof formula A10, which are a subset of the examples of formula A3, areoutlined in Scheme 3. In this case, a phenol building block of formulaA1 is treated with a suitable 3-chloro-6-chloromethyl-pyridazine A8 toprovide an chloropyridazine intermediate of formula A9.Chloromethyl-pyridazines of formula A9 are commercially available or canbe made according to known procedures from the literature. The couplingreaction is performed in the presence of a base and under conditionswhich are described above. Intermediate A10 can be converted to thedesired pyridazinones of formula A3 using different methods. Method a,for example, is based on the treatment of A9 with a suitable base suchas NaOH, KOH or similar in the presences of water or solvent containingsome water at temperatures ranging from −20° C. to the boiling point ofthe solvents used to afford the desired pyridaziones of formula A10.Alternatively, according to method b, conversion of A9 to A10 is alsopossible for example by treatment of A9 with a carboxylic acid such asacetic acid, formic acid or similar, at temperatures ranging from 0° C.to 150° C., followed by aqueous workup.

Further Elaboration of Suitable Compounds of Formula A3

In some cases, the coupling reaction between phenol A1 and buildingblock A2 produces a bicyclic intermediate such as for example thioetherA11 (Scheme 4). All can be used to introduce for example suitablesolubilizing groups that further alter the overall properties of thecompounds. To achieve this, the protecting group PG of A11 is removed bythe appropriate treatment depending on the nature of PG: for example,Boc, trityl of THP groups can be all removed by treatment with strongacids such as HBr, HCl. TFA or the like in an appropriate solvent suchas dioxane, water, ethanol, methanol or DCM or the like at temperaturesranging from −20° C. to the boiling point of the solvent. Subsequentlyafter removal of PG, the intermediate is oxidized to providemethylsulfone A12. Suitable oxidizing agents are for example m-CPBA inDCM, oxone in MeOH/H₂O, H₂O₂, KMnO₄ in water/AcOH or many others.Treatment of A12 with a suitable amine NR_(F)R_(F′) as defined in Scheme4, which can be in excess, in a solvent such as THF orN-methylpyrrolidone or DMSO or the like at temperatures ranging from 0°C. to the boiling point of the solvent or up to 200° C. in a sealed tubeor microwave will provide aminopyrimidines of formula A13.

Alternatively. A12 can be treated with an appropriate alcohol HO—R_(H)(suitably protected as THP presence of a base such as NaH, KH, Cs₂CO₃,Na₂CO₃ or the like in a suitable solvent such as DMF. THF, DMA ordioxane or the like at temperatures ranging from 0° C. to the boilingpoint of the solvent, to provide a compound of formula A14. Any sidechain protecting groups can easily be removed by treatment with an acidsuch as TFA in DCM for a THP group or for example aqueous HCl for anacetonide to provide the desired unprotected compounds of formula A15.

Similar to what was described above for pyrimidines, a protectedfluoropyridine of formula A16 (PG=trityl or Boc) (Scheme 5) can betreated with an appropriate alcohol HO—R_(H) (suitably protected as THPethers or acetonides if it contains multiple OH groups, as defined inScheme 5) in the presence of abase such as NaH, KH, Cs₂CO₃, Na₂CO₃ orthe like in a suitable solvent such as DMF, DMA THF or the like attemperatures ranging from 0° C. to the boiling point of the solvent, toprovide a substituted hydroxypyridine of formula A17. Any protectinggroups on the pyrazole (PG=e.g. trityl, Boc, PMB) and any side chainprotecting groups (THP, acetonide or similar) can easily be removed bytreatment with an acid such as TFA in DCM or for example with aqueousHCl, HBr or the like to provide the desired unprotected compounds offormula A18.

In some cases, the coupling reaction between phenol A1 and buildingblock A2 produces a suitably protected bicyclic intermediate such as forexample pyrazolopiperidines A19 (Scheme 6). These compounds carry forexample a Boc group at the piperidine nitrogen Y¹ or Y² and optionally aprotecting group PG on the pyrazole, which, as described above can befor example Boc, trityl, THP or similar. For further elaboration, allprotecting groups are removed under the appropriate conditions such asTFA in DCM or HCl in dioxane or similar to provide the unprotectedpiperidine derivative A20. In order to obtain suitable compounds forthis invention, A19 is treated with an acid chloride in the presence ofa base such as NEt₃, Huenigs base, pyridine or the like in a solventsuch as DCM, DMF, dioxane or similar to provide the desired substitutedpiperidines of formula A21 which are defined as shown in Scheme 6. Thelatter transformation is also possible with carboxylic acids that areactivated in many other different ways; suitable conditions are wellknown to those skilled in the art.

In some cases, the coupling reaction between phenol A1 and buildingblock A2 produces a suitably protected pyrazole-carboxylic acid esterA22 (Scheme 7). While such a compound is itself an example of a compoundof formula (I) after the usual removal of the pyrazole protecting groupPG, the ester group is also useful for further elaboration. A22 can forexample be treated with a suitable amine NR_(P)R_(P′) in the presence ofAlMe₃ in a proper solvent such as DCM, CH₃Cl, THF or dioxane or similarat temperatures ranging from −20° C. to the boiling point of the solventto provide a carboxylic acid amide of formula A23. Removal of thepyrazole protecting group under the appropriated conditions mentionedabove will then provide the desired pyrazole-carboxylic acid amide A34,which is an example of a compound of formula (I) and in which thesubstituents R_(P) and R_(P′) are defined by R_(D4) in the claim.

General Synthesis of Specific Subsets of Intermediates of Formula A2Used in this Invention

A) Substituted Triazolones

Triazolone intermediates of formula B5 in which R_(D1) can be morecomplex than methyl are a subset of compounds of formula A2 and can bemade according to the sequence that is shown in Scheme 8. A suitablyN-substituted hydrazinecarboxamide of formula B1 which is commerciallyavailable or can be made according to methods known in the literature istreated with benzyloxyacetylchloride B2 and an aqueous base such asNaOH, KOH, K₂CO₃ or similar in a suitable solvent such as THF or thelike to provide a protected triazolone intermediate of formula B3. Thisintermediate can be easily de-benzylated using conditions known in theart that include for example hydrogenation with suitable catalysts suchas Pd/C, PtO₂, Pd(OH)₂/C or similar in solvents such as methanol, aceticacid, ethyl acetate or even water to provide the hydroxymethylintermediate B4. Introduction of the leaving group X to provide thedesired building block B5 is affected using suitable conditions whichare dependent on the leaving group to be introduced. If, for example,X=Cl, intermediate B4 can be treated with COCl₂ to provide B5 with X=Cl.If, for example, X=Br, treatment with CBr₄ and PPh₃ could be used. IfX=mesylate or tosylate, then 54 could be treated with the appropriatesulfonyl chloride (methanesulfonyl chloride orp-toluenesulfonylchloride) in the presence of a base such astrietylamine, pyridine, DMAP, Huenig's base or similar in a suitablesolvent such as CH₂Cl₂ or THF or similar at temperatures ranging from−78° C. to the boiling point of the solvent to provide B5 in whichR_(D1) is defined according to the claims.

B) 1H-Pyrazolo Pyridines, Pyrazolo Pyrimidines, Indazoles and Similar

Appropriately functionalized Pyrazolo pyridines, pyrazolo pyrimidinesand indazoles B13 are again a subset of the building blocks of formulaA2 that are used in this invention to make compounds of formula (I)(Scheme 9A). Suitable precursors for the synthesis of these bicycliccompounds of formula B13 are commercially available or can be madeaccording to procedures that are described in the literature. Forexample, it is possible to use indazolones or aza-indazolones B6 asstarting materials. Such compounds are commercially available or can bemade new. An example for making a new compound of formula B6 will begiven further below. To elaborate B6, the material can be treated withPOBr₃ to obtain the brominated intermediate B7. The chloro derivativemay also be envisioned although it might be less reactive in thesubsequent transformations: in this case the appropriate reagent has tobe applied (e.g. POCl₃ for the chloro derivative). Intermediate B7 isthen protected at the nitrogen with an appropriate protecting group PGto provide B8. PG can for example be a PMB group or a trityl group orsimilar. Suitable conditions which are dependent on the nature of theprotecting group to be introduced have to be applied; e.g. for PG=PMBchloromethyl-4-methoxybenzene in the presence of a base such as Cs₂CO₃,Na₂CO₃ or similar in a solvent such as DMF, THF or CH₃CN or similar attemperatures ranging from 0° C. to the boiling point of the solvent, orfor PG=trityl chlorodiphenylmethyl-benzene in the presence of a basesuch as triethylamine. Huenig's base, Na₂CO₃ or CS₂CO₃ or similar in asolvent like THF, DMF or similar at temperatures ranging from 0° C. tothe boiling point of the solvent. To obtain ester B10 from bromide B8,the material is treated with carbon monoxide in the presence ofmethanol, a suitable Pd catalyst such as for example Pd(OAc)₂ and anappropriate ligand such as for example 1,3-bis(diphenylphosphino)-propan(dppp) in a suitable solvent such as DMF and the appropriatetemperature. Depending on the position of the nitrogen(s) and thesubstituent RE, suitable esters B9 might be commercially available andcan be converted to the desired intermediate B10 using conditions asdescribed above for the conversion of B7 to B8. To be able to introducea leaving group at the exocyclic carbon, the ester group of B10 can bereduced to the alcohol B11 using conditions well known in the art suchas LiBH₄ or NaBH₄ in MeOH, EOH or THF or similar or DIBAL in toluene orDCM or similar at temperatures ranging from −20° to the boiling point ofthe solvent. Note that in some cases and depending on the conditions andnature of the heterocycle of B10 some overreduction may be observed,providing compound B12. If this happens, re-oxidation with anappropriate oxidation agent [Ox] such as for example chloranil and ananhydrous solvent such as toluene, benzene or DCM can re-create B11. Toobtain the desired intermediate B13 which is exemplified here with abromide as a leaving group, B11 can be treated for example with PBr₃ oralternatively with CBr₄ in the presence of PPh₃ in a suitable solventsuch as CH₃CN or DCM or similar. Other leaving groups such as a chlorideor mesylate or tosylate may also be possible; conditions to make thoseare known to those skilled in the art.

Starting materials of formula 36 are either commercially available orcan be made according to Scheme 9B if a specific substitution pattern isneeded. In the particular example shown below, the suitably substitutedprecursor B14 is treated with hydrazine in ethanol to provide hydrazideB15. Treatment of B15 with a base such as aqueous NaOH or KOH solutionwith heating will provide the corresponding indazolone derivative B16,which can be subjected to the synthetic steps indicated above.

C) Pyrazolopiperidines

Appropriately functionalized pyrazolo piperidines (one Y=N-Boc) ortetrahydroindazoles (both Y=CH₂) B19 are another subset of the buildingblocks of formula A2 that are used in this invention to make compoundsof formula (I) (Scheme 1A). Suitable precursors for the synthesis ofthese bicyclic compounds of formula B19 are commercially available orcan be made according to procedures that are described in theliterature. A suitable precursor or intermediate is for example a anester of formula B17, which are may be protected with a suitableprotecting group PG such as for example Boc or trityl. Such esters canbe reduced to the hydroxymethyl derivative B18 using appropriatereducing agents such as NaBH₄. LiBH₄ or DIBAL or similar in solventssuch as MeOH, EtOH, THF or similar. As described above, introduction ofthe leaving group X to provide the desired building block B19 isaffected using suitable conditions which are dependent on the leavinggroup to be introduced. If, for example, X=Cl, intermediate B18 can betreated with COCl₂ to provide B19 with X=Cl. If, for example, X=Br,treatment with CBr₄ and PPh₃ could be used. If X=mesylate or tosylate,then B18 could be treated with the appropriate sulfonyl chloride(methanesulfonyl chloride or p-toluenesulfonylchloride) in the presenceof a base such as trietylamine, pyridine, DMAP, Huenig's base or similarin a suitable solvent such as CH₂Cl₂ or THF or similar at temperaturesranging from −78° C. to the boiling point of the solvent to providebuilding block B19.

If a suitable starting material B17 is not commercially available, whichcan be the case for some of the pyrazolopiperidines with one Y=N-Boc,then one possible synthetic approach is outlined in Scheme 10B.Commercially available Boc-piperidin-4-one B20 is subjected to an aldoltype reaction with ethyl diazoacetate and a suitable base such as LDA,LiHMDS or the like in a solvent such as THF or ether or similar attemperatures ranging from −78° C. to the boiling point of the solvent toprovide intermediate B21. B21 can be dehydrated to provide B22, a stepthat is performed by treatment with a common dehydrating agent such asPOCl₃ or similar. Cyclization of B22 to provide the desiredpyrazolopiperidine B23 is achieved for example by heating of B22 in asolvent like toluene or xylene or similar up to the boiling point of thesolvent. Alternatively, if a solvent with a lower boiling point such asTHF or benzene or similar is used, the transformation may be done in asealed tube or for example in a microwave.

D) Pyrazoles and Pyrazole-Carboxylic Acid Derivatives

Appropriately functionalized pyrazols B26 or B29 are another subset ofsuitable building blocks of formula A that are used in this invention tomake compounds of formula (I) (Scheme 11). Suitable precursors for thesynthesis of compounds of formula B26 and B29, respectively, arecommercially available or can be made according to procedures that aredescribed in the literature. As outlined in Scheme 11A, a suitableprecursor is methylpyrazole B24, which can be protected forexampleithdi-tert-butyldicarbonateunderconditionsthatarewellknowntothose skilled in the art to provide the Boc-protected intermediate B25.Other protecting groups instead of Boc may be used in thistransformation, as exemplified below in the synthesis for B29. To obtainthe desired building block B26 with a leaving group, intermediate B25 istreated with NBS and dibenzoylperoxide in CCl₄ to provide thebromomethyl building block B26.

If pyrazoles with some additional substitution are desired, they can bemade for example from the commercially available diester B27 (Scheme11B). B27 can be protected for example as a hemi-aminal with THP: inthis case B27 is treated with dihydropyran and TFA or another suitableacid such as p-tolenesulfoninic acid or similar in a solvent such as DCMor THF or the like to provide the protected diester intermediate B28Asingle ester group can then be reduced with DIBAL in solvent such astoluene, benzene or DCM at temperatures ranging from −78° C. to theboiling point of the solvent to give hydroxymethyl derivative B29. Inanalogy to what was described for other building blocks, introduction ofthe leaving group X to provide the desired building block B30 isaffected using suitable conditions which are dependent on the leavinggroup to be introduced. If, for example, X=Cl, intermediate B29 can betreated with COCl₂ to provide B30 with X=Cl. If, for example, X=Br,treatment with CBr₄ and PPh₃ could be used. If X=mesylate or tosylate,then B29 could be treated with the appropriate sulfonyl chloride(methanesulfonyl chloride or p-toluenesulfonylchloride) in the presenceof a base such as trietylamine, pyridine, DMAP, Huenig's base or similarin a suitable solvent such as CH₂Cl₂ or THF or similar at temperaturesranging from −78° C. to the boiling point of the solvent to providebuilding block B30.

General Synthesis of Phenol Building Blocks of Formula A1 Used in thisInvention

Introduction and Elaboration of Ortho Substituent R_(A) with R_(A)≠Aryl

In this section, the synthesis of various phenol building blocks of thegeneral formula A1 is described. While R_(A) designates the substituentin ortho position to the OH group, R_(B) is a substituent hat needs tobe introduced that may need further elaboration during the synthesis andR_(C) are one or several substituents that are present from thebeginning and are carried through the synthesis. For some of thepreferred phenol intermediates with the ortho-substituentR_(A)=tert-butyl, access is possible based on the corresponding phenollacking the R_(A) substituent. In these cases as outlined in Scheme 12,a suitable phenol precursor C1 without the ortho-substituent R_(A) isthen treated for example with tert-butanol (C2, X=OH) as a precursor ofthe tert-butyl substituent in the presence of a strong acid such assulfuric acid or p-toluenesulfonic acid, phosphoric acid or the like ina suitable solvent such as acetic acid or similar at temperaturesranging from room temperature to the boiling point of the solvent or ateven higher temperatures up to 250° C. for example in a sealed tube orin a microwave to provide a o-tert-butylphenol of formula C3. Othersources for the tert-butyl substituent such as isobutylene,2-chloro-2-methylbutane (C2; X=Cl), 2-bromo-2-methylbutane (C2; X=Br),tert-butylmethylether (C2; X=OMe), or similar can also be used in such atransformation and suitable additives such as AlCl₃ or ZnCl₂ can be usedto promote the reaction. Depending on the substitution pattern of thestarting material, regioisomers may be obtained that need to beidentified and separated.

A possible synthesis of phenol intermediates with R_(A) substituentsthat are different from tert-butyl or iso-butyl can be accomplished asoutlined in Scheme 13. A key intermediate is for example an iodide ofstructure C6 which is suitably protected with a PG (for example, PG canbe a methyl group, a benzyl group or a MOM group or similar, dependingon the compatibility of the protecting group with the conditions to beused in the synthesis) (Scheme 13A). In the context of this invention,C6 can be made from a commercially available, suitably protectednitrophenol C4, which can be reduced to the corresponding aniline C5 bymethods and reagents (indicated by [red]) well known in the literaturesuch as reduction by catalytic hydrogenation using hydrogen gas and asuitable catalyst such as Pd on carbon or similar or other reductiveconditions such as zinc dust or iron in the presence of a weak acid suchas ammonium chloride solution or acetic acid in suitable solvents suchas water, ethanol, methanol or mixtures thereof. Introduction of theiodine is accomplished using well known conditions such as for exampletreatment of C5 with sodium nitrite and potassium iodide in water underheating to provide intermediate C6.

As outlined in Scheme 13B, aliphatic or alicyclic R_(A) residues canthen be introduced by treating precursor C6 with a suitable aliphatic oralicyclic boronate or borolane C7 (M=B(OH)₂ or B(OR)₂) and anappropriate catalyst such as Pd(OAc)₂ or PdCl₂ or similar in thepresence of an suitable ligand such as triphenylphosphine,tricyclohexylphosphine or the like in a solvent such as DMF, water ortoluene or mixtures thereof at temperatures ranging from roomtemperature to 150° C. to provide coupling products C8. In some casessuch as for example if R_(A)=cyclopropyl, then the protecting group canbe removed to provide the desired phenol building block C9 directly.Conditions for the removal of PG will depend on the nature of PG: If PGis methyl, then the removal can be accomplished for example by treatmentof C8 for example with BBr₃ in a solvent such as DCM or the like toprovide C9. If, for example PG is a benzyl group, then removal will beaccomplished for example with catalytic hydrogenation (e.g. Pd/C, H₂gas). If PG=MOM, then removal will be accomplished for example by acidtreatment (e.g. aq HCl in THF or similar).

In other cases, if C8 contains a double bond (e.g. cyclohexenyl,dihydopyranyl or propenyl), reduction of the double bond can be easilyaccomplished with catalytic hydrogenation under conditions describedbefore (e.g. H₂, Pd/C) to obtain intermediates C8A. Then again, removalof PG from C8A to obtain building blocks of formula C9 will be done asdescribed above for intermediate C8.

An alternative approach to introduce certain R_(A)-substituents isoutlined in Scheme 13C). In this approach, iodide C6 is treated firstwith isopropylmagnesiumchloride, resulting in iodine-magnesium exchange,followed by addition of a suitable ketone C10 in inert solvents such asTHF or ether or similar at temperatures ranging from −78° C. to theboiling point of the solvent, to provide tertiary alcohol C11. Reductionof the tertiary alcohol C11 to provide aliphatic or alicyclicintermediate C12 can be done using conditions known in the literature;e.g. by treatment by BF₃OEt₂ and triethylsilane in solvents such as DCMor CHCl₃ or the like at temperatures ranging from −78° C. to the boilingpoint of the solvent. Again, PG removal from C12 to provide buildingblocks of formula C9 can be done as described above for C8 and C8A,respectively.

Introduction and Elaboration of R_(B)—Synthesis of Various Intermediates

In many cases in the context of this invention, suitable startingmaterials are commercially available or easily accessible that alreadybear the desired ortho-substituent R_(A). In these cases, introductionand elaboration of the desired substituent R_(B) in the proper positionis required, while other substituents R_(C) might be present and areusually carried through the synthesis unchanged. Depending on the natureof R_(B) to be introduced, different precursors are required and thephenolic hydroxy group needs to be suitably protected in order to becompatible with the anticipated reaction conditions (Scheme 14). Forexample, suitable starting points are commercially availablephenylbromides C13 with R_(A) being in the scope of the claims asdefined within formula (I). C13 can be O-protected to provide C14:suitable protecting groups PG are for example methyl, benzyl or MOM.Conditions for introduction vary depending on the nature of PG, butusually a base such as Cs₂CO₃, NaH, Na₂CO₃ or the like in a suitablesolvent such as DMF, DMSO, THF or CH₃CN or the like as well as a reagentfor the protecting group such as MeI, benzylchloride or -bromide orMOM-Cl at temperature ranging from −20° to the boiling point of thesolvent are used for this transformation. A cyano group can then beintroduced to provide arylnitrile C15, using conditions well known inthe art. Zn(CN)₂, in the presence of zinc,1,1′-bis(diphenylphosphino)ferrocen (dppf) and Pd₂(dba)₃ in solventslike DMF at temperatures ranging from room temperature up to the boilingpoint of the solvent or alternatively conditions such as CuCN inanhydrous DMF at elevated temperatures up to the boiling point of DMFare examples for suitable conditions for this transformation.

The cyano group can be hydrolyzed to provide free carboxylic acid C16;suitable conditions comprise the presence of aqueous NaOH or KOHsolution in solvents such as EtOH or MeOH or the like at temperaturesranging from 0° C. to the boiling point of the solvent. While thecarboxylic acid C16 itself can be a useful intermediate for furtherelaboration towards R_(B), an ester group might be preferable. To obtainfor example a methyl ester C17, C16 can be treated with a base such asCs₂CO₃, NaH or K₂CO₃ or the like followed with MeI in a solvent such asDMF, DMSO, THF or CH₂CN or the like temperatures ranging from 0° C. tothe boiling point of the solvent. Alternatively, treatment with a strongacid (catalytic up to stoichiometric amounts) such as H₂SO₄ orp-toluenesulfonic acid in boiling methanol with or without a water trapcan achieve the same transformation to ester C17.

Introduction and Elaboration of R_(B) Based on Bromides of Formula C14

One way to elaborate R_(B) based on arylbromides C14 is the use of Pdcatalyzed coupling reactions such as Suzuki, Stille or Buchwaldreactions or similar. Suitable conditions to achieve thesetransformations have been extensively reviewed in the literature. Threeoptions to obtain intermediates C18 are shown in Scheme 15, wherebromide C14 is either treated with M-HET, which can for example be aheterocyclic stannane such as 2-tributylstannyl oxazole (Stilleconditions) or a heterocyclic boronate or borolane such as1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolane-2-yl-1H-imidazole(Suzuki conditions), or alternatively for Buchwald conditions with anitrogen containing heterocycle such as morpholine. In terms ofconditions, Stille reactions can be done using for example catalystslike PdCl₂(dppf)₂ DCM complex or the like in solvents such as dioxane orthe like, whereas Suzuki type reactions can be with PdCl₂(dppf)₂ DCMcomplex in the presence of a base such as Na₂CO₃ or K₂CO₃ or the like insolvents such as DMF. Buchwald reactions can be done with catalysts suchas Pd₂(dba)₃ and a suitable ligand such xantphos in the presence of abase such as potassium tert-butlylate in solvents such as anhydroustoluene. In all cases the reactions are done at temperatures rangingfrom room temperature to 150° C. (or higher, if sealed tubes are used).Removal of the protecting groups PG of C18 to obtain phenols C19 can bedone as described above for compounds of formula C8 or C8A.

In some special cases where the desired heterocyclic stannane orboronate building blocks are not accessible, stepwise elaboration may benecessary to introduce the desired heterocyles starting from bromideC14. An example for such a stepwise approach is given in Scheme 16.Treatment of bromide C14 in a Heck type reaction with n-butyl vinyletherin the presence of a Pd catalyst such as Pd(OAc)₂ or PdCl₂ or similarand a bidentate ligand such as bis(diphenylphosphino)propane and a basesuch as K₂CO₃ or the like in a solvent like water or DMF or mixturesthereof at temperatures ranging from room temperature up to 200° C.followed by acidic workup using aqueous mineral acids such as HCl or HBror similar will provide acetyl derivative C20. Subsequently, treatmentof C20 with bromine itself or alternatively with a bromine source suchas Bu₄NBr₃ in a solvent such as THF, ether, dioxane or the like willprovide bromoacetyl intermediate C21. This intermediate can be convertedto the desired imidazole derivative C22 by treatment with excessformamide at temperatures ranging from 100-200° C. IN this case, inorder to be able to perform the coupling step shown in Scheme 1, asuitable protection of the imidazole heterocycle is required. While anumber of different suitable protecting groups can be envisioned (see:Green and Wuts., Protecting Groups in Organic Synthesis, J. Wiley &Sons), Scheme 16 shows the use of the SEM group, which can be introducedto C22 by treatment with SEMCl and a suitable base such as NaH,KO^(t)Bu, LDA or Cs₂CO₃ or similar in THF, ether or DMF or similar attemperatures ranging from −20° C. to the boiling point of the solvent toprovide protected imidazole C23. Removal of the protecting groups PG ofC23 to obtain phenols C24 to be used in the coupling reaction with thebuilding blocks of formula A2 can be done as described above in forcompounds of formula C8 or C8A.

An option for the introduction of a sulfone residue R_(B) to bromidesC14 is shown in Scheme 16. To achieve this transformation, C14 istreated for example with sodium sulfonate and in the presence of acopper complex which is preformed from copper iodide and L-proline inthe presence of abase sodium hydroxide or the like. The couplingreaction to provide sulfones of formula C25 is done in solvents such asDMSO or similar at temperatures ranging from room temperature to 130° C.Removal of the protecting group PG of C25 to obtain phenols C26 can bedone as described above for compounds of formula C8 or C8A.

Introduction and Elaboration of R_(B) Based on Carboxylic Acid Esters ofFormula C17

Carboxylic acid esters of formula C17 are other possible precursors forthe introduction and/or elaboration of R_(B), if R_(B) is for example acertain type of heterocycle. An example of such an approach is shown inScheme 18A. According to this strategy, C17 is treated with a base suchas NaH, Cs₂CO₃, Na₂CO₃ or similar followed by N-hydroxyacetamidine in asolvent such as DMF, THF or similar at temperatures ranging from −20° C.to the boiling point of the solvent. This treatment will provide thecorresponding 1,2,4-oxadiazole C27, which can be de-protected to providephenol C28 under suitable conditions which are depending on the natureof PG as described above for C8 and C8A.

An alternative route to introduce heterocyclic substituents to arylesterstarting materials C17 is outlined in Scheme 18B. In this particularcase, the protecting group PG on the phenol has already been removedearlier, for example at the stage of C17, providing the de-protectedester C29. This material can be treated with hydrazine in a solvent likemethanol, ethanol, DMSO or water or similar at temperatures up to 100°C. to provide acylhydrazide C30. To obtain the desired 1,3,4-oxadiazolesC31, C30 can be treated with an excess of carboxylic acid ortho ester(e.g. trimethylorthoaceate for R_(Q)=Me) at temperatures up to 200° C.It is conceivable to use other carboxylic acid ortho esters, which mayresult in compounds of formula C31 with heterocyclic substituents thatcarry an R_(Q) other than methyl.

Introduction and Elaboration of R_(B) Based on Nitriles of Formula C15

Aryl nitriles of formula C32 are other possible precursors for theintroduction and/or elaboration of R_(B), if R_(B) is for exampleanother type of heterocycle. i.e. certain imidazole derivatives. Anexample of such an approach is shown in Scheme 19. According to thisstrategy, arylnitrile C15 is treated initially with excessethylenediamine and P₂S₅ in a sealed tube at temperatures from roomtemperature to 150° C. to provide dihydroimidazole C32. C32 can beoxidized with an appropriate oxidation agent [Ox] to provide imidazolederivative C33. Appropriate oxidation agents and conditions are forexample diazetoxy-iodobenzene/K₂CO₃/DMSO, KMnO₄/Al₂O₃/CH₃CN, isocyanuricchloride/DBU/CH₃CN. The imidazol nitrogen of C32 can then be alkylatedwith an alkylating agent R_(R)—X, where R_(R) is for example an alkylgroup and X is a leaving group such as iodine or bromine or tosylate inthe presence of a base such as NaH, Cs₂CO₃ or Na₂CO₃ or similar in asolvent such as DMF, THF. CH₃CN or similar at temperatures from −20° C.to the boiling point of the solvent to provide the N-alkylatedintermediate C34. Alternatively, R_(R) can also be a protecting groupsuch as SEM or MOM or the like (orthogonal to phenol protecting groupPG) that can be removed again later to recreate the free imidazole at anappropriate stage. Removal of the protecting group PG of C34 to obtainphenols C35 to be used in the coupling reaction with head groups offormula A2 can be done as described above for compounds of formula C8 orC8A.

While the approaches outlined above show the preferred routes to many ofthe intermediates and examples shown in this invention, some specificcompounds with special substitution patterns can be made via alternativeroutes, again depending on the precursors that are convenientlyavailable or accessible. For example, introduction of nitrile groups cannot only be done as shown earlier in Scheme 14, but nitriles can also beformed by dehydration for carboxylic acid amides (Scheme 20). If theprotecting group is removed at the stage of primary amide, then theresulting phenols can also be used as intermediates of formula A1.

Introduction and Elaboration of Both R_(A) and R_(B)

In some specific cases and particularly if there is a need to introduceand elaborate both R_(A) and R_(B), more complex routes that includeprotecting group strategies have to be worked out in addition to theones described above to be able to produce suitable phenol intermediatesof formula A1. Such a route to an intermediate is outlined in Scheme 21Abelow.

A suitable starting material is for example C40 that contains anaryl-amine and substituent X (X=e.g. Br, I) besides R_(C) and the OHgroup. C40 is protected for example with di-tert-butyldicarbonate in thepresence of a base such as NEt₃, Huenig's base, DMAP or pyridine orsimilar in a solvent such as DCM, THF or ether or the like attemperatures from −20° C. to the boiling point of the solvent providethe tris-Boc intermediate C41. R_(A) can now be introduced for exampleby using an appropriate boronic acid or borolane C42 in the presence ofan appropriate catalyst such as Pd(OAc)₂ or PdCl₂ or similar in thepresence of an suitable ligand such as triphenylphosphine,tricyclohexylphosphine or the like in a solvent such as DMF, water ortoluene or mixtures thereof at temperatures ranging from roomtemperature to 150° C. to provide coupling products C43 carrying theappropriate R_(A) substituent. Removal of the Boc protecting groups isthen easily possible using standard acid treatment such as for exampleTFA in DCM, HCl in dioxane or similar or aq. HCl, at appropriatetemperatures, to provide amino-hydroxy intermediate C44. One example offurther elaboration of the amino group consists of treatment with sodiumnitrite in water in the presence of an acid such as H₂SO₄ or HCl orsimilar, followed by potassium iodide, to provide iodide C45. It is thenpossible to introduce for example a cyano group by treatment of C45 withCuCN in a solvent such as DMF or DMSO or the like at temperatures fromroom temperature to 150° C. to provide nitrile C46 with R_(B)═CN.Alternatively, the amino group of intermediate C44 can be modifieddifferently, for example by acylation as shown in Scheme 21 bysulfonylation. For sulfonylation, C44 is treated with the appropriatesulfonyl chloride C47 (R_(F) is for example small alkyl) in the presenceof a base such as pyridine, DMAP, NEt₃ or Hunig's base in a solvent suchas DMF, DCM, or THF at temperatures ranging from −20° C. to the boilingpoint of the solvent, followed by treatment with NAOH, KOH or LiOH inwater, to provide sulfonamide C48 with R_(B)═NHSO₂R_(F).

Another option of introducing both R and R_(B) is shown in Scheme 21B.In this particular case, phenol C101 can be chlorinated for example inpara-position to the hydroxyl group with a chlorinating agent such asN-chloro-succinimide in the presence of a strong acid such as triflicacid or the like in an acidic solvent such as acetic acid or formic acidor similar at temperatures ranging from room temperature to the boilingpoint of the solvent. A person skilled in the art will acknowledge thatthe site of chlorination may be dependent on the other substituentspresent on the aryl ring of C101. Usually, it will be required toprotect the free hydroxyl group of the product C102 for furtherelaboration, providing intermediate C103. Suitable protecting groups PGsuch benzyl or MOM or SEM or similar as well as conditions forintroduction have been discussed above. Introduction of R_(A) whichcorresponds to a 2-methyl-propionitril-2-yl group in this case can beachieved for example by treatment of C103 with isobutyronitrile in thepresence of a non-nucleophilic strong base such as KHMDS or NaHMDS in asolvent such as toluene or benzene or the like in a sealed tube attemperatures ranging from room temperature to 160° C. to provideintermediate C104 with the desired substitution pattern. Conditions forremoval of the protecting group PG of C104 to obtain phenol C105 to beused in the coupling reaction with head groups of formula A2 will bedependent on the nature of PG and can be done as described above forcompounds of formula C8 or C8A.

Introduction and Elaboration of Ortho Substituent R_(A) for Phenols C49with R_(A)=Substituted Aryl

The general sequences depicted in Schemes 22-29 may be of considerablelength and a person skilled in the art will acknowledge that thesequence of reactions steps as depicted in Schemes 22 to 29 may bevaried depending on reactivity and nature of the intermediates. Similarto what was described earlier, if one of the starting materials orintermediates contain one or more functional groups which are not stableor are reactive under the reaction conditions of one or more reactionsteps, appropriate protecting groups (as described, e.g. in “ProtectiveGroups in Organic Chemistry” by T. W. Greene and P. G. M. Wutts, 5thEd., 2014, John Wiley & Sons, N.Y.) can be introduced before thecritical step applying methods well known in the art. Such protectinggroups can be removed at a later stage of the synthesis using standardmethods described in the literature.

Synthesis of phenol intermediates C49 in which R_(A) signifies anoptionally substituted aryl or heteroaryl substituent can beaccomplished, for example, as outlined in Scheme 22 from intermediatesC6 which are commercially available or can be prepared as describedunder Scheme 13. Reaction of C6 with (substituted) boronic acidsR_(A)—B(OH)₂ or boronic esters R_(A)—B(OR′)₂ (e.g. pinacol ortrimethylene glycol ester, either commercially available or preparedusing literature procedures as described for example in “BoronicAcids—Preparation and Applications in Organic Synthesis and Medicine” byDennis G. Hall (ed.) 1st Ed., 2005, John Wiley & Sons, New York) using asuitable catalyst (e.g.dichloro[1,1′-bis(diphenylphosphino)-ferrocene]palladium(II)dichloromethane adduct, tetrakis(triphenylphosphine)palladium(0) orpalladium(II) acetate with triphenylphosphine) in an appropriate solvent(e.g. dioxane, dimethoxyethane, water, toluene, N,N-dimethylformamide ormixtures thereof) and a suitable base (e.g. sodium carbonate, sodiumhydrogen carbonate, potassium fluoride, potassium carbonate ortriethylamine) at temperatures between room temperature and the boilingpoint of the solvent or solvent mixture yields intermediates C50 (stepa). Suzuki reactions of this type are broadly described in literature(e.g. A. Suzuki. Pure Appl. Chem. 1991, 63, 419-422; A. Suzuki, N.Miyaura, Chem. Rev. 1995, 95, 2457-2483; A. Suzuki, J. Organomet. Chem.1999, 576, 147-168; V. Polshettiwar et al., Chem. Sus. Chem. 2010, 3,502-522) and are well known to those skilled in the art. Alternatively,aryl- or heteroaryl-trifluoroborates R_(A)BF₃K can be used in thecross-coupling reaction applying a palladium catalyst such as, e.g.tetrakis(triphenylphosphine) palladium(0), palladium(II) acetate ordichloro[1,1′-bis(diphenylphosphino)ferrocene]-palladium(II)dichloromethane adduct in the presence of a suitable base such as cesiumcarbonate or potassium phosphate in solvents such as toluene, THF,dioxane, water or mixtures thereof, at temperatures between roomtemperature and the boiling point of the solvent or solvent mixture.

Intermediates C50 can be also synthesized from C6 with (substituted)aryl- or heteroaryl tin reagents R_(A)—SnR₃ (R=e.g. Me or n-Bu; eithercommercially available or prepared according to literature procedures)in the presence of a suitable catalyst (e.g.tetrakis-(triphenylphosphine)palladium(0),benzylbis(triphenylphosphine)-palladium(II) chloride,bis(triphenylphosphine)palladium(II) dichloride ordichloro[1,1′-bis(diphenylphosphino)-ferrocene]palladium(II)dichloromethane adduct) in an appropriate solvent such as THF, dioxane,DMF (N,N-dimethylformamide) or HMPA (hexamethylphosphoramide) ormixtures thereof) at temperatures between room temperature and theboiling point of the solvent or solvent mixture, optionally in thepresence of lithium chloride. Stille couplings of this type are broadlydescribed in literature (e.g. J. K. Stille, Angew. Chem. Int. Ed. Engl.1986, 25, 508-524; V. Farina et al., J Org. React. 1998, 50, 1-652; T.N. Mitchell, Synthesis 1992, 9, 803-815) and well known to those skilledin the art (step a).

Alternatively, intermediates C50 can be synthesized from reaction ofintermediates C6 with (substituted) aryl- or heteroaryl zinc halidesR_(A)—ZnX (X=Cl, Br or I) (either commercially available or synthesizedby methods described in literature) using a nickel (e.g.tetrakis(triphenylphosphine)nickel(0)) or palladium catalyst (e.g.tetrakis(triphenylphosphine) palladium(0)) in an appropriate solventsuch as, e.g. THF or DMA in a temperature range between room temperatureand boiling point of the solvent. Negishi couplings of this type arebroadly described in literature (e.g. “Name Reactions forHomologations-Part I: Negishi cross-coupling reaction”, Li, J. J.,Corey, E. J., Eds.; Wiley & Sons, Hoboken, N.J., 2009, 70-99;“Metal-Catalyzed Cross-Coupling Reactions”, Diederich. F.; Stang, P. J.,Eds.; Wiley-VCH: Weinheim, Germany, 1998, 1-47; E. Erdik, Tetrahedron1992, 48, 9577-9648; G. Organ, Eur. J. Org. Chem. 2010, 4343-4354) andwell known to those skilled in the art (step a). Removal of theprotecting group PG in intermediates C50 by methods known to thoseskilled in the art and as described for example in “Protective Groups inOrganic Chemistry” by T. W. Greene and P. G. M. Wutts, 5th Ed., 2014,John Wiley & Sons, N.Y. (e.g. a benzyl group by hydrogenation using asuitable catalyst such as palladium on carbon in an appropriate solventsuch as MeOH, EtOH, EtOAc or mixtures thereof; a methyl group byreaction with boron tribromide in an appropriate solvent such asdichloromethane) furnishes intermediates C49 (step b), which are asubset of the desired phenol building blocks of formula A1.

Intermediates C51 may also be prepared from intermediates C6 by firstremoving the protective group PG from intermediates C6 using theconditions described before (step c) and converting the resultingintermediates C51 into intermediates C49 by applying for example Suzuki,Stille or Negishi cross-coupling reactions as described above (step d).

If the building blocks (i.e. the substituted aryl or heteroaryl boronicacids R_(A)—B(OH)₂ or boronic esters, aryl- or heteroaryl tin reagentsR_(A)—SnR₃, or (substituted) aryl- or heteroaryl zinc halides R_(A)—ZnX)for the preparation of intermediates C49 from intermediates C6 are notcommercially available or unstable under the reaction conditionsapplied, intermediates C49 can be alternatively prepared according tothe procedures described below.

For example, intermediates C56 and C58 in which R_(A) signifies a phenylring appropriately substituted with R_(G1) (see claims) and substitutedby a secondary or tertiary amide functionality can be synthesizedaccording to Scheme 23. Cross-coupling reactions between phenyl boronicacids or aryl boronic esters C52 substituted with a carboxyl or estergroup and with R_(G1) that corresponds to a substituent according to theclaims, either commercially available or which can be synthesized bymethods known to persons skilled in the art, with intermediate C6 underthe reaction conditions described under Scheme 22, step a, yields biarylintermediates C53 (step a). Cleavage of the carboxylic acid esterfunctionality in intermediates C53 under basic (e.g. methyl or ethylesters with lithium or sodium hydroxide in polar solvents such asmethanol, H₂O or THF or mixtures of said solvents) or neutral conditions(e.g. a benzyl group Bn by hydrogenation using a suitable catalyst suchas palladium on carbon in an appropriate solvent such as MeOH, EtOH,EtOAc or mixtures thereof) furnishes intermediates C54 (step b). Furtheresters include, but are not limited to, e.g. allyl esters that can becleaved by methods known to those skilled in the art and as describedfor example in “Protective Groups in Organic Chemistry” by T. W. Greeneand P. G. M. Wutts, 5th Ed., 2014, John Wiley & Sons, N.Y., applying anorthogonal protecting group strategy that will allow removal of theester protective group without affecting other protecting groups such asthe phenol protective group PG. Reaction of intermediates C54 withamines of the type R^(c)—NH₂ furnishes intermediates C55 (step c). Amidecouplings of this type are widely described in the literature and can beaccomplished by the usage of coupling reagents such as, e.g., CDI, DCC,HATU, HBTU, HOBT, TBTU or Mukaiyama reagent in a suitable solvent, e.g.,DMF, DMA, DCM or dioxane, optionally in the presence of a base (e.g.,NEt₃, DIPEA (Huenig's base) or DMAP). Alternatively, in a two-stepprocedure, the carboxylic acid functionality in intermediates C54 can beconverted into its acid chloride by treatment with, e.g. thionylchloride, neat or optionally in a solvent such as DCM. Reaction of theacid chloride with R^(c)—NH₂ in an appropriate solvent such as DCM orDMF and a base, e.g. NEt₃, Huenig's base, pyridine, DMAP or lithiumbis(trimethylsilyl)amide at temperatures ranging from 0° C. to thereflux temperature of the solvent or solvent mixture yieldsintermediates C55 (step c). Removal of the protective group PG of C55applying the methods described before furnishes intermediates C56 (stepd).

Intermediates C58 can be prepared as well from intermediates C54 bycoupling with secondary amines of the type R^(c)R^(d)NH by applying thereaction conditions described above to give the tertiary amide C57 (stepe). Subsequent removal of the protective group PG by applying thereaction conditions outlined before furnishes intermediates C58 (stepf).

Intermediates C57 can alternatively be prepared by alkylation ofintermediates C55 with compounds R^(d)-LG in which LG signifies asuitable leaving group such as bromo (or another leaving group such aschloro, iodo or OSO₂alkyl, OSO₂fluoroalkyl, OSO₂aryl) using anappropriate base and solvent such as sodium hydride in tetrahydrofuranto furnish intermediates C57 (step g). Amide substituents R^(c), R^(d)used in Scheme 23 are defined by the appropriate subset of substituentsof R_(G) as defined in the claims.

Intermediates C63 in which R_(A) signifies a phenyl ring appropriatelysubstituted with R_(G1) and substituted by an alkoxy, haloalkoxy,arylalkoxy or heteroarylalkyoxy substituent can be synthesized forexample according to Scheme 24. Alkylation of bromo-phenols C59,optionally substituted with R_(G1) as defined by the scope of theclaims, which are either commercially available or can be prepared bymethods known to those skilled in the art, with compounds of the typeR_(S)LG in which R_(S) is defined by a subset of the scope of R_(G) inthe claims and LG signifies a suitable leaving group such as bromo (oranother leaving group such as chloro, iodo or OSO₂alkyl,OSO₂fluoroalkyl, OSO₂aryl) using an appropriate base and solvent such aspotassium carbonate in acetone or sodium hydride in tetrahydrofuranyields intermediates C60 (step a). Intermediates C60 can be converted tothe corresponding boronic acids or boronic acid esters C61 usingliterature procedures as described for example in “BoronicAcids—Preparation and Applications in Organic Synthesis and Medicine” byDennis G. Hall (ed.) 1st Ed., 2005, John Wiley & Sons, New York, forexample using 4,4,4′,5,5,5′5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane(CAS RN 73183-34-3) in the presence of a suitable base, catalyst andsolvent system such as potassium acetate,[1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) complexwith dichloromethane in 1,4-dioxane at temperatures ranging from roomtemperature to the boiling point of the solvent or solvent mixture (stepb). Suitable conditions for cross-coupling reaction of intermediates C61with intermediate C6 (step c) were described above. Removal of theprotective group PG in intermediates C62 by applying literatureprocedures or the reaction conditions outlined before furnishesintermediates C63 (step d).

Intermediates C62 can alternatively be prepared from intermediates C67by applying an orthogonal protecting group strategy (removal of oneprotecting group, in any order, using reagents and conditions that donot affect other protecting groups in the target compound). The hydroxygroup in optionally substituted bromo-phenols C59 can be protected bymethods known to those skilled in the art and as described for examplein “Protective Groups in Organic Chemistry” by T. W. Greene and P. G. M.Wutts, 5th Ed., 2014, John Wiley & Sons, N.Y. (e.g. a methoxymethyl(MOM) group by reacting the optionally substituted bromo-phenols withmethoxymethyl chloride in the presence of a base in a suitable solventsuch as NaH in THF at temperatures ranging from 0° C. to the boilingpoint of the solvent) to give intermediates C64 (step e). IntermediatesC64 in turn can be converted into intermediates Cl₁₆ (step f) asoutlined above under step b. Subsequent cross-coupling of intermediatesC65 with intermediates C6 (step g) by applying the reaction conditionsdescribed above for step c furnishes intermediates C66. Selectiveremoval of the protective group PG′ in intermediates C66 on theoptionally substituted phenyl substituent R_(A) yields intermediates C67(step h). Intermediates C67 in turn can be transformed intointermediates C62 through alkylation with compounds of the type R_(S)-LGin which R_(S) is defined by a subset of the scope of R_(G) in theclaims and LG signifies a suitable leaving group such as bromo (oranother leaving group such as chloro, iodo or OSO₂alkyl,OSO₂fluoroalkyl, OSO₂aryl) and using the reaction conditions describedbefore yields intermediates C113 (step i).

Intermediates C74 in which R_(A) signifies a phenyl ring appropriatelysubstituted with R_(G) and connected via a methylene (CH₂) linker to anN-linked lactam or cyclic urethane can be synthesized for exampleaccording to Scheme 25. The benzylic alcohol function in startingmaterial C68 which are either commercially available or can be preparedreadily according to literature procedures can be converted to asuitable leaving group LG such as bromo (e.g. by reacting intermediatesC119 with tetrabromomethane in the presence of triphenylphosphine in THFas solvent) or another leaving group such as chloro, iodo or OSO₂alkyl.OSO₂fluoroalkyl, OSO₂aryl, to give intermediates C69 (step a). Reactionof intermediates C69 with lactams or cyclic urethanes C68 in thepresence of a suitable base and solvent system such as sodium hydride inDMF yields intermediates C71 (step b). Intermediates C71 can beconverted to their corresponding boronic acids or boronic esters C72using common literature procedures as described for example in “BoronicAcids—Preparation and Applications in Organic Synthesis and Medicine” byDennis G. Hall (ed.) 1st Ed., 2005, John Wiley & Sons, New York, forexample using 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane(CAS RN 73183-34-3) in the presence of a suitable base, catalyst andsolvent system such as potassium acetate,[1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) complexwith dichloromethane in 1,4-dioxane, at temperatures ranging from roomtemperature to the boiling point of the solvent or solvent mixture (stepc). Cross-coupling reaction of intermediates C72 with intermediate C6under the reaction conditions described before yields intermediates C73(step d). Removal of the protective group PG in intermediates C73 byapplying literature procedures or the reaction conditions outlinedbefore furnishes intermediates C74 (step e). Intermediates C74 can bealso prepared from cross-coupling reactions of intermediates C72 withbuilding block C51 by applying the methods described before (step f.

Intermediates C79 and C83 in which R_(A) signifies a phenyl ringappropriately substituted with R_(G1) and which is connected via amethylene (CH₂) linker to an N-linked secondary or tertiary carboxylicacid amide group can be synthesized for example according to Scheme 26.Acylation of the amine group in benzylic amines C75 which are eithercommercially available or can be readily prepared according toliterature procedures, with carboxylic acids of the type R_(T)—COOHfurnishes intermediates C76 (step a). Amide couplings of this type arewidely described in the literature and can be accomplished by the usageof many different coupling reagents such as, e.g., CDI, DCC, HATU, HBTU,HOBT, TBTU or Mukaiyama reagent in a suitable solvent, e.g., DMF, DMA,DCM or dioxane, optionally in the presence of a base (e.g., NEt₃, DIPEA(Huenig's base) or DMAP). Alternatively, the carboxylic acids R_(T)—COOHcan be converted into their acid chlorides before the coupling reactionby treatment with, e.g. thionyl chloride, neat or optionally in asolvent such as DCM. Reaction of the acid chloride with intermediatesC75 in an appropriate solvent such as DCM or DMF and a base, e.g. NEt₃,Huenig's base, pyridine, DMAP or lithium bis(trimethylsilyl)amide attemperatures ranging from 0° C. to the reflux temperature of the solventor solvent mixture yields compounds C76 (step a). Intermediates C76 canbe converted into their boronic acids or boronic ester intermediates C77using literature procedures as described for example in “BoronicAcids—Preparation and Applications in Organic Synthesis and Medicine” byDennis G. Hall (ed.) 1st Ed., 2005, John Wiley & Sons, New York andapplying methods described before (step b). Cross-coupling ofintermediates C77 with intermediates C6 using the reaction conditionsdescribed before yields intermediates C78 (step g). Removal of theprotective group PG in intermediates C78 is done by applying literatureprocedures or the reaction conditions described before to giveintermediates C79 (step d).

Intermediates C83 in which R_(A) signifies a phenyl ring which isconnected via a methylene (CH₂) linker to an N-linked tertiary amidegroup can be prepared from intermediates C76 for example by N-alkylationof intermediates C76 with compounds of the type R_(U)-LG in which LGsignifies a suitable leaving group such as bromo (or another leavinggroup such as chloro, iodo or OSO₂alkyl, OSO₂fluoroalkyl, OSO₂aryl)using an appropriate base and solvent such as sodium hydride intetrahydrofuran to furnish intermediates C80 (step e). In analogy to thedescription above for C76, C77, C78 and C79 intermediates C80 can beconverted into intermediates C81 (step f), C82 (step e) and finally C83(step h) applying the methods described before. Intermediates C81 canalternatively also be prepared by alkylation of intermediates C77 withcompounds of the type R_(U)-LG and applying the conditions describedunder step e above (step i). Intermediates C82 can be also prepared byalkylation of intermediates C78 with compounds of the type R_(U)-LG andapplying the conditions described under step e above (step j). BothR_(T) and R_(U) used in Scheme 26 are defined by the appropriate subsetof substituents of the scope of R_(G) as outlined in the claims.

Intermediates C49 in which R_(A) signifies an aryl ring which is furthersubstituted by a heteroaryl ring and for which the suitable boronicacids R_(A)—B(OH)₂ or boronic esters R_(A)—B(OR′)₂, tin reagentsR_(A)—SnR₃ or zinc halides R_(A)—ZnX for the introduction ofsubstituents R_(A) into intermediates CC6 or C51 are not available orunstable under the reaction conditions to be applied, intermediates C49can be synthesized for example according to Schemes 27 to 29 and bymethods described in literature. Persons skilled in the art willacknowledge that this methodology is also applicable to a variety ofother heteroaryl systems.

For example, intermediates C87 in which R_(A) signifies a phenyl ringappropriately substituted with R_(G1) and substituted by a[1.3.4]oxadiazol-2-yl ring in which R_(V) is for example alkyl,cycloalkyl, trifluoromethyl, benzyl or phenyl or similar, can beprepared from intermediates C53 (see Scheme 23 for preparation)according to Scheme 27. Selective cleavage of the carboxylic acid esterfunctionality in intermediates C53 (e.g. methyl or ethyl esters withlithium or sodium hydroxide in polar solvents such as methanol, H₂O orTHF or mixtures of said solvents; further esters include, but are notlimited to, e.g. benzyl or allyl esters that can be cleaved by methodsknown to those skilled in the art and as described for example in“Protective Groups in Organic Chemistry” by T. W. Greene and P. G. M.Wutts, 5th Ed., 2014, John Wiley & Sons, N.Y.) and in which R^(a) ischosen in such a way that the hydroxyl protective group PG is notaffected under the reaction conditions applied for the cleavage of R^(a)(“orthogonal protecting group strategy”) furnishes intermediates C84(step a). Reaction of intermediates C84 with acylhydrazines of the typeR_(V)—C(O)NHNH₂ yields intermediates C85 (step b). Amide couplings ofthis type are widely described in the literature and can be accomplishedby the usage of coupling reagents such as, e.g., CDI, DCC, HATU, HBTU,HOBT, TBTU or Mukaiyama reagent in a suitable solvent, e.g., DMF, DMA,DCM or dioxane, optionally in the presence of a base (e.g., NEt₃, DIPEA(Huenig's base) or DMAP). Alternatively, the carboxylic acidfunctionality in intermediates C84 can be converted into its acidchloride by treatment with, e.g. thionyl chloride, neat or optionally ina solvent such as DCM. Reaction of the acid chloride with acylhydrazines of the type R_(V)—C(O)NHNH₂ in an appropriate solvent such asDCM or DMF and a base, e.g. NEt₃, Huenig's base, pyridine, DMAP orlithium bis(trimethylsilyl)amide at temperatures ranging from 0° C. tothe reflux temperature of the solvent or solvent mixture yields the1,2-diacyl hydrazide intermediates C85 (step b). Cyclization of thediacyl hydrazide group in intermediates C135 using a suitablecyclodehydration agent such as POCl₃, SOCl₂, Burgess reagent ordiethylaminodifluorosulfinium tetrafluoroborate (XtalFluor-E®) eitherneat or using an appropriate solvent such as dichloromethane, optionallyin the presence of an acid such as acetic acid at temperatures rangingfrom room temperature to the boiling pint of the solvent or solventmixture, furnishes the 1,3,4-oxadiazole intermediates C86 (step c).Synthesis of this type of 1,3,4-oxadiazoles is well known in the art andhas been also described in literature, e.g. M.-F. Pouliot el al., Org.Biom. Chem. 2012, 10(5), 988. Removal of the protective group PG of C86to provide C87 is done by methods known to those skilled in the art andas described for example in “Protective Groups in Organic Chemistry” byT. W. Greene and P. G. M. Wutts, 5th Ed., 2014, John Wiley & Sons, N.Y.(e.g. a benzyl group by hydrogenation using a suitable catalyst such aspalladium on carbon in an appropriate solvent such as MeOH, EtOH, EtOAcor mixtures thereof: a methyl group by reaction with boron tribromide inan appropriate solvent such as dichloromethane) (step d).

Intermediates C93 in which R_(A) signifies a phenyl ring appropriatelysubstituted with R_(G1) and substituted by a [1.2.4]oxadiazol-5-yl ringin which R_(W) is for example alkyl, cycloalkyl, trifluoromethyl, benzylor phenyl or similar can be prepared according to Scheme 28 for examplefrom intermediates C88. Syntheses of [1.2.4]oxadiazoles are broadlydescribed in literature, for example in R. O. Bora et al., Mini-ReviewsMed. Chem. 2013, 13 or K. Hemming, Sci. Synthesis 2004, 13, 127. Nitrileintermediates C88 which are either commercially available or can beprepared by methods well known in the art, can be converted into theirboronic esters such as pinacol esters C89 by literature procedures, forexample by reaction of intermediates C88 with pinacol in a suitablesolvent such as THF (step a). The cyano functionality in intermediatesC89 can be transformed into an amidoxime group by methods known in theart, for example by reaction with hydroxylamine (optionally as itshydrochloride salt) in a suitable solvent such as EtOH in the presenceof a base like, e.g. Huenig's base to give intermediates C90 (step b).Cyclization of the amidoxime functionality in intermediates C90 with anactivated carboxylic acid derivative carrying the substituent R_(W) suchas the corresponding acid anhydride, acid chloride, acid ester or orthoester at temperatures ranging from room temperature to the boiling pointof the solvent yields intermediates C91 which are often obtained withoutisolation of the intermittently formed O-acylated amidoxime intermediate(step c). Intermediates C91 can be reacted with intermediates C6 incross-coupling reactions using the conditions described under Scheme 22,step a, to furnish intermediates C92 (step d). Removal of the protectivegroup in intermediates C92 by methods known to those skilled in the art,as described for example in “Protective Groups in Organic Chemistry” byT. W. Greene and P. G. M. Wutts, 5th Ed., 2014, John Wiley & Sons, N.Y.and as described before furnishes the desired phenol intermediates C93(step e).

Intermediates C92 can alternatively be prepared from intermediates C88by performing cross-coupling reactions with intermediate C6 as the firststep of the sequence as described under Scheme 22, step a, to giveintermediates C94 (step f), then conversion of the cyano group into anamidoxime functionality using the methods described above to provide C95(step g) and then cyclization of C95 with an activated carboxylic acidcarrying substituent R_(W) under the conditions outlined before to giveintermediates C92 (step h). Intermediates C94 can also be prepared fromintermediates C89 by cross-coupling reaction with intermediates C6 byapplication of the reaction conditions described before (step i).

Intermediates C100 in which R_(A) signifies a phenyl ring appropriatelysubstituted with R_(G1) and substituted by a tert-butyl protected1H-pyrazol-3-yl group can be prepared for example as depicted in Scheme29. Cross-coupling of intermediates C96, either commercially availableor prepared according to literature procedures, with intermediates C6,applying the methods described under Scheme 22 (step a), yieldsintermediates C97 (step a). The acetyl group in intermediates C97 can betransformed into a 3-dimethylamino-acryloyl group applying publishedprocedures, for example by reaction with N,N-dimethylformamide dimethylacetal, preferentially at elevated temperatures, to give intermediatesC98 (step b). Reaction of C98 with tert-butyl hydrazine in a suitablesolvent such as ethanol or methanol or similar, preferably at elevatedtemperatures furnishes pyrazole intermediates C99 (step c).Chemoselective removal of the phenol protective group PG inintermediates C99 by applying an orthogonal protective group strategy asoutlined before provides intermediates C100 (step d).

Alkylation of the phenol group of C100 with the desired head group A2 asdescribed under Scheme 1 and subsequent removal of the tert-butylprotecting group of the pyrazole by methods known in the art and asdescribed for example in “Protective Groups in Organic Chemistry” by T.W. Greene and P. G. M. Wutts, 5th Ed., 2014, John Wiley & Sons, N.Y.(e.g. a tert-butyl group under acidic conditions such as HCl in dioxanein a suitable solvent such as dichloromethane) furnishes the finalproducts of formula A3.

Also an embodiment of the present invention is a process to prepare acompound of formula (I) as defined above comprising the reaction of acompound of formula (II) in the presence of a compound of formula (III);

wherein R_(A), R_(B), R_(C) and W are as defined herein and X ishalogen, mesylate or tosylate.

In particular, in the presence of abase, particularly in the presence ofpotassium carbonate, optionally in the presence of potassium iodide, ina solvent such as acetone and at a temperature comprised between −78° C.and reflux, particularly between room temperature and reflux.

Also an object of the present invention is a compound according toformula (I) as described herein for use as a therapeutically activesubstance.

Likewise an object of the present invention is a pharmaceuticalcomposition comprising a compound according to formula (I) as describedherein and a therapeutically inert carrier.

A particular embodiment of the present invention is a compound accordingto formula (I) as described herein for the treatment or prophylaxis ofocular conditions, particularly glaucoma.

The present invention also relates to the use of a compound according toformula (I) as described herein for the preparation of a medicament forthe treatment or prophylaxis of ocular conditions, particularlyglaucoma.

Also an object of the invention is a method for the treatment orprophylaxis of ocular conditions, particularly glaucoma, which methodcomprises administering an effective amount of a compound according toformula (I) as described herein.

Renal conditions include, but are not limited to, acute kidney injuryand chronic renal disease with and without proteinuria includingend-stage renal disease (ESRD). In more detail, this includes decreasedcreatinine clearance and decreased glomerular filtration rate,micro-albuminuria, albuminuria and proteinuria, glomerulosclerosis withexpansion of reticulated mesangial matrix with or without significanthypercellularity (particularly diabetic nephropathy and amyloidosis),focal thrombosis of glomerular capillaries (particularly thromboticmicroangiopathies), global fibrinoid necrosis, ischemic lesions,malignant nephrosclerosis (such as ischemic retraction, reduced renalblood flow and renal arteriopathy), swelling and proliferation ofintracapillary (endothelial and mesangial) and/or extracapillary cells(crescents) like in glomerular nephritis entities, focal segmentalglomerular sclerosis, IgA nephropathy, vasculitides/systemic diseases aswell as acute and chronic kidney transplant rejection.

Liver conditions include, but are not limited to, liver cirrhosis,hepatic congestion, cholestatic liver disease including pruritus,nonalcoholic steatohepatitis and acute and chronic liver transplantrejection.

Inflammatory conditions include, but are not limited to, arthritis,osteoarthritis, multiple sclerosis, systemic lupus erythematodes,inflammatory bowel disease, abnormal evacuation disorder and the like aswell as inflammatory airways diseases such as idiopathic pulmonaryfibrosis (IPF), chronic obstructive pulmonary disease (COPD) or chronicasthma bronchiale.

Further conditions of the respiratory system include, but are notlimited to, other diffuse parenchymal lung diseases of differentetiologies including iatrogenic drug-induced fibrosis, occupationaland/or environmental induced fibrosis, systemic diseases andvasculitides, granulomatous diseases (sarcoidosis, hypersensitivitypneumonia), collagen vascular disease, alveolar proteinosis, Langerhanscell granulomatosis, lymphangioleiomyomatosis, inherited diseases(Hermansky-Pudlak Syndrome, tuberous sclerosis, neurofibromatosis,metabolic storage disorders, familial interstitial lung disease),radiation induced fibrosis, silicosis, asbestos induced pulmonaryfibrosis or acute respiratory distress syndrome (ARDS).

Conditions of the nervous system include, but are not limited to,neuropathic pain, schizophrenia, neuro-inflammation (e.g. astrogliosis),peripheral and/or autonomic (diabetic) neuropathies and the like.

Vascular conditions include, but are not limited to, atherosclerosis,thrombotic vascular disease as well as thrombotic microangiopathies,proliferative arteriopathy (such as swollen myointimal cells surroundedby mucinous extracellular matrix and nodular thickening),atherosclerosis, decreased vascular compliance (such as stiffness,reduced ventricular compliance and reduced vascular compliance),endothelial dysfunction and the like.

Cardiovascular conditions include, but are not limited to, acutecoronary syndrome, coronary heart disease, myocardial infarction,arterial and pulmonary hypertension, cardiac arrhythmia such as atrialfibrillation, stroke and other vascular damage.

Fibrotic diseases include, but are not limited to myocardial andvascular fibrosis, renal fibrosis, liver fibrosis, pulmonary fibrosis,skin fibrosis, scleroderma and encapsulating peritonitis.

Cancer and cancer metastasis include, but are not limited to, breastcancer, ovarian cancer, lung cancer, prostate cancer, mesothelioma,glioma, hepatic carcinoma, gastrointestinal cancers and progression andmetastatic aggressiveness thereof.

Ocular conditions include, but are not limited to, proliferative andnon-proliferative (diabetic) retinopathy, dry and wet age-relatedmacular degeneration (AMD), macular edema, central arterial/venousocclusion, traumatic injury, glaucoma and the like. Particularly, theocular condition is glaucoma.

Metabolic conditions include, but are not limited to, obesity anddiabetes.

Also an embodiment of the present invention provides compounds offormula (I) as described herein, when manufactured according to any oneof the described processes.

Assay Procedures

Production of Human Full Length ATX, with and without His Tag

Autotaxin (ATX—ENPP2) cloning: cDNA was prepared from commercial humanhematopoietic cells total RNA and used as template in overlapping PCR togenerate a full length human ENPP2 ORF with or without a 3′-6×His tag.These full length inserts were cloned into the pcDNA3.1V5-His TOPO(Invitrogen) vector. The DNA sequences of several single clones wereverified. The DNA from a correct full length clone was used to transfectHek293 cells for verification of protein expression. The sequence of theencoded ENPP2 conforms to Swissprot entry Q13822, with or without theadditional C-terminal 6×His tag.

ATX Fermentation: Recombinant protein was produced by large-scaletransient transfection in 20 L controlled stirred tank bioreactors(Sartorius). During cell growth and transfection, temperature, stirrerspeed, pH and dissolved oxygen concentration were maintained at 37° C.,120 rpm, 7.1 and 30% DO, respectively. FreeStyle 293-F cells(Invitrogen) were cultivated in suspension in FreeStyle 293 medium(Invitrogen) and transfected at ca. 1-1.5×10E6 cells/mL with aboveplasmid DNAs using X-tremeGENE Ro-1539 (commercial product, RocheDiagnostics) as complexing agent. Cells were fed a concentrated nutrientsolution (J Immunol Methods 194 (1996), 19, 1-199 (page 193)) andinduced by sodium butyrate (2 mM) at 72 h post-transfection andharvested at 96 h post-transfection. Expression was analyzed by WesternBlot, enzymatic assay and/or analytical IMAC chromatography. Aftercooling the cell suspension to 4° C. in a flow-through heat exchanger,cell separation and sterile filtration of supernatant was performed byfiltration through Zeta Plus 60M02 E16 (Cuno) and Sartopore 2 XLG(Sartorius) filter units. The supernatant was stored at 4° C. prior topurification.

ATX Purification: 20 liter of culture supernatant were conditioned forultrafiltration by adding Brij 35 to a final concentration of 0.02% andby adjusting the pH to 7.0 using 1 M HCl. Then the supernatant was firstmicrofiltred through a 0.2 μm Ultran-Pilot Open Channel PES filter(Whatman) and afterwards concentrated to 1 liter through an Ultran-PilotScreen Channel PES filter with 30 kDa MWCO (Whatman). Prior to IMACchromatography, NiSO₄ was added to a final concentration of 1 mM. Thecleared supernatant was then applied to a HisTrap column (GE Healthcare)previously equilibrated in 50 mM Na₂HPO₄ pH 7.0, 0.5 M NaCl, 10%glycerol, 0.3% CHAPS, 0.02% NaN₃. The column was washed stepwise withthe same buffer containing 20 mM, 40 mM and 50 mM imidazole,respectively. The protein was subsequently eluted using a lineargradient to 0.5 M imidazole in 15 column volumes. ATX containingfractions were pooled and concentrated using an Amicon cell equippedwith a 30 kDa PES filter membrane. The protein was further purified bysize exclusion chromatography on Superdex S-200 prep grade (XK 26/100)(GE Healthcare) in 20 mM BICINE pH 8.5, 0.15 M NaCl, 10% glycerol, 0.3%CHAPS, 0.02% NaN₃. Final yield of protein after purification was 5-10 mgATX per liter of culture supernatant. The protein was stored at −80° C.

Human ATX Enzyme Inhibition Assay

ATX inhibition was measured by a fluorescence quenching assay using aspecifically labeled substrate analogue (MR121 substrate). To obtainthis MR121 substrate, BOC and TBS protected 6-amino-hexanoic acid(R)-3-({2-[3-(2-{2-[2-(2-amino-ethoxy)-ethoxy]-ethoxy}-ethoxy)-propionylamino]-ethoxy}-hydroxy-phosphoryloxy)-2-hydroxy-propylester (Ferguson et al., Org Lett 2006, 8 (10), 2023) was labeled withMR121 fluorophore (CAS 185308-24-1,1-(3-carboxypropyl)-11-ethyl-1,2,3,4,8,9,10,11-octahydro-dipyrido[3,2-b:2′,3′-i]phenoxazin-13-ium)on the free amine of the ethanolamine side and then, after deprotection,subsequently with tryptophan on the side of the aminohexanoic acid.

Assay working solutions were made as follows:

Assay buffer (50 mM Tris-HCl, 140 mM NaCl, 5 mM KCl, 1 mM CaCl₂, 1 mMMgCl₂, 0.01% Triton-X-100, pH 8.0;

ATX solution: ATX (human His-tagged) stock solution (1.08 mg/mL in 20 mMbicine, pH 8.5, 0.15 M NaCl, 10% glycerol, 0.3% CHAPS, 0.02% NaN₃),diluted to 1.4-2.5× final concentration in assay buffer;

MR121 substrate solution: MR121 substrate stock solution (800 μM MR121substrate in DMSO), diluted to 2-5× final concentration in assay buffer.

Test compounds (10 mM stock in DMSO, 8 μL) were obtained in 384 wellsample plates (Corning Costar #3655) and diluted with 8 μL DMSO.Row-wise serial dilutions were made by transferring 8 μL cpd solution tothe next row up to row O. The compound and control solutions were mixedfive times and 2 μL were transferred to 384 well assay plates (CorningCostar #3702). Then, 15 μL of 41.7 nM ATX solution was added (30 nMfinal concentration), mixed five times and then incubated for 15 minutesat 30° C. 10 μL of MR121 substrate solution was added (1 μM finalconcentration), mixed 30 times and then incubated for 15 minutes at 30°C. Fluorescence was then measured every 2 minutes for 1 hour (PerkinElmer plate: vision multimode reader); light intensity: 2.5%; exp. time:1.4 sec, Filter: Fluo_630/690 nm) and IC₅₀ values were calculated fromthese readouts.

ATX Example Ic50 [μM] A 1 0.002 A 2 0.01 A 3 0.025 A 4 0.059 A 6 0.523 A7 0.013 A 8 1.6 A 9 2.613 A 10 0.104 A 11 0.015 A 12 0.001 A 13 0.002 A14 1.891 A 15 0.23 A 16 0.005 A 17 0.035 A 19 0.015 A 20 0.008 A 210.062 A 22 0.173 A 23 >27 A 24 0.091 A 25 0.958 A 26 0.012 A 27 0.019 A28 0.005 A 29 0.05 A 30 0.009 A 31 0.019 A 32 3.768 A 34 0.028 B 1 0.003B 2 0.001 B 3 0.001 B 4 0.006 B 5 0.003 B 6 0.008 B 7 4.195 B 8 0.01 B 90.012 B 10 0.023 B 11 0.166 B 12 0.022 B 13 0.006 B 14 0.079 B 15 0.011B 16 0.025 B 17 0.016 B 18 0.052 B 19 0.065 B 20 0.913 B 21 0.104 B 220.227 B 23 0.212 B 24 0.126 B 25 0.02 B 26 0.495 B 27 3.717 B 28 5.941 B29 0.078 B 30 0.467 B 31 0.043 B 32 0.031 B 33 0.115 B 34 0.051 B 350.081 B 36 0.082 B 37 0.079 B 38 0.008 B 39 0.093 B 40 0.015 B 41 0.040B 42 0.021 B 43 1.102 B 44 0.013 B 45 0.029 B 46 0.007 B 47 0.082 B 480.192 B 49 0.008 B 50 0.173 B 51 0.017 B 52 0.012 B 53 0.042 B 54 0.029B 55 0.009 B 56 0.015 B 57 0.011 B 58 0.016 B 59 0.025 B 60 0.011 B 610.01 B 62 0.009 B 63 0.01 B 64 0.021 B 65 0.013 B 66 0.007 B 67 0.006 B68 0.007 B 69 0.009 B 70 0.004 B 71 0.009 B 72 0.010 B 73 0.009 B 740.006 B 75 0.01 B 76 0.011 B 77 0.015 B 78 0.007 B 79 0.010 B 80 0.005 B81 0.003 B 82 0.008 B 83 0.008 B 84 0.019 B 85 0.021 B 86 0.049 B 870.005 B 88 0.001 B 89 0.004 B 90 0.007 B 91 0.004 B 92 0.001 B 93 0.005B 94 0.005 B 95 0.006 B 96 0.037 B 97 0.008 B 98 0.009 C 1 0.019 C 20.022 C 3 0.004 C 4 0.003 C 5 0.001 C 6 0.007 C 7 0.022 C 8 0.005 C 90.046 C 10 0.032 C 11 5.978 C 12 0.003 C 13 0.04 C 14 0.005 D 1 244.592D 2 0.014 D 3 0.004 D 4 0.009 D 5 0.001 D 6 0.019 D 7 0.012 D 8 0.006 D9 0.215 D 10 >82 D 11 0.0045 D 12 0.001 D 13 13.186 D 14 0.013 D 150.006 D 16 0.018 D 17 0.002 D 18 0.017 D 19 0.035 D 20 0.022 D 21 0.009D 22 0.01 D 23 0.021 D 24 0.099 D 25 0.018 D 26 0.014 D 27 0.008 D 280.098 D 29 0.01 D 30 0.009 D 31 0.007 D 32 0.008 D 33 0.006 D 34 0.002 D35 0.009 D 36 0.008 D 37 0.006 D 38 0.009 D 39 0.008 D 40 0.006 D 410.007 D 42 0.006 D 43 0.007 D 44 0.009 D 45 0.023 D 46 0.004 D 47 0.011D 48 0.032 D 49 0.002 D 50 0.001 D 51 0.069 D 52 0.002 D 53 0.008 D 540.028 D 55 0.003 E 1 0.746 E 2 41.319 E 3 80.381 E 4 0.019 E 5 0.017 E 60.015 E 7 0.202 E 8 0.069 F 1 0.027 F 2 0.018 F 3 0.01 F 4 0.008 F 50.015

Compounds of formula (I) and their pharmaceutically acceptable salts oresters thereof as described herein have IC₅₀ values between 0.00001 μMand 1000 μM particular compounds have IC₅₀ values between 0.0005 μM and500 μM, further particular compounds have IC₅₀ values between 0.0005 μMand 50 μM, more particular compounds have IC₅₀ values between 0.0005 μMand 5 μM. These results have been obtained by using the enzymatic assaydescribed above.

The compounds of formula (I) and their pharmaceutically acceptable saltscan be used as medicaments (e.g. in the form of pharmaceuticalpreparations). The pharmaceutical preparations can be administeredinternally, such as orally (e.g. in the form of tablets, coated tablets,dragées, hard and soft gelatin capsules, solutions, emulsions orsuspensions), nasally (e.g. in the form of nasal sprays), rectally (e.g.in the form of suppositories) or topical ocularly (e.g. in the form ofsolutions, ointments, gels or water soluble polymeric inserts). However,the administration can also be effected parenterally, such asintramuscularly, intravenously, or intraocularly (e.g. in the form ofsterile injection solutions).

The compounds of formula (I) and their pharmaceutically acceptable saltscan be processed with pharmaceutically inert, inorganic or organicadjuvants for the production of tablets, coated tablets, dragées, hardgelatin capsules, injection solutions or topical formulations Lactose,corn starch or derivatives thereof, talc, stearic acid or its salts etc.can be used, for example, as such adjuvants for tablets, dragées andhard gelatin capsules.

Suitable adjuvants for soft gelatin capsules, are, for example,vegetable oils, waxes, fats, semi-solid substances and liquid polyols,etc.

Suitable adjuvants for the production of solutions and syrups are, forexample, water, polyols, saccharose, invert sugar, glucose, etc.

Suitable adjuvants for injection solutions are, for example, water,alcohols, polyols, glycerol, vegetable oils, etc.

Suitable adjuvants for suppositories are, for example, natural orhardened oils, waxes, fats, semi-solid or liquid polyols, etc.

Suitable adjuvants for topical ocular formulations are, for example,cyclodextrins, mannitol or many other carriers and excipients known inthe art.

Moreover, the pharmaceutical preparations can contain preservatives,solubilizers, viscosity-increasing substances, stabilizers, wettingagents, emulsifiers, sweeteners, colorants, flavorants, salts forvarying the osmotic pressure, buffers, masking agents or antioxidants.They can also contain still other therapeutically valuable substances.

The dosage can vary in wide limits and will, of course, be fitted to theindividual requirements in each particular case. In general, in the caseof oral administration a daily dosage of about 0.1 mg to 20 mg per kgbody weight, preferably about 0.5 mg to 4 mg per kg body weight (e.g.about 300 mg per person), divided into preferably 1-3 individual doses,which can consist, for example, of the same amounts, should it beappropriate. In the case of topical administration, the formulation cancontain 0.001% to 15% by weight of medicament and the required dose,which can be between 0.1 and 25 mg in can be administered either bysingle dose per day or per week, or by multiple doses (2 to 4) per day,or by multiple doses per week It will, however, be clear that the upperor lower limit given herein can be exceeded when this is shown to beindicated.

The invention is illustrated hereinafter by Examples, which have nolimiting character.

In case the preparative examples are obtained as a mixture ofenantiomers, the pure enantiomers can be obtained by methods describedherein or by methods known to those skilled in the art, such as e.g.chiral chromatography or crystallization.

EXAMPLES

All examples and intermediates were prepared under nitrogen atmosphereif not specified otherwise.

Abbreviations: aq.=aqueous; CAS: =Chemical Abstracts Service RegistryNumber; HPLC=high performance liquid chromatography; MS=mass spectrum;sat.=saturated; rt=room temperature; TLC=thin layer chromatography; NMR:nuclear magnetic resonance spectrum;

Intermediates A

Intermediate A2:

2-tert-Butyl-4-chloro-5-fluorophenol

To a solution of 4-chloro-3-fluorophenol (CAS: 2713-33-9; 1.14 g) inacetic acid (6.0 mL) were added tert-butanol (1.73 g), followed bysulfuric acid (1.53 g) at rt under an argon atmosphere. The mixture wasthen heated to 80° C. for 17 hours. TLC showed that the reaction was notcomplete and thus the reaction was refluxed (88° C.) for another 30hours. While there was still some starting material visible on TLC, thereaction mixture was cooled down to rt and poured into ice/water. Theaqueous phase was then extracted two times with ethyl acetate and thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered and evaporated. The crude material was purified by flashchromatography on silica gel with a gradient of 0% to 25% EtOAc inheptane as an eluent, to provide the title compound as a brown liquid(320 mg). MS (m/z): 201.1 [M−H]⁻.

Intermediate A4:

2-tert-Butyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)phenol

Step 1: 1-Benzyloxy-4-bromo-2-tert-butyl-benzene

This material which is known in the literature (CAS: 33839-12-2) wasmade as follows:

To a solution of 4-bromo-2-tert-butyl-phenol (CAS: 10323-39-4; 8 g) inanhydrous acetonitrile (150 mL) was added Cs₂CO₃ (22.7 g) followed bybenzyl bromide (6.26 mL) at 25° C. and the mixture was stirred at 85° C.for 3 h. The reaction mixture was cooled to 25° C., filtered and thefiltrate was evaporated under reduced pressure. The resulting residuewas purified by column chromatography over silica gel (gradient of 3-5%ethyl acetate in hexanes) to provide1-benzyloxy-4-bromo-2-tert-buty-benzene (11.0 g) as an off white solid.¹H-NMR (400 MHz, S, DMSO-D6): 1.32 (s, 9H), 5.14 (s, 2H), 7.04 (d, 1H),7.28-7.50 (m, ˜7H).

Step 2: 4-Benzyloxy-3-tert-butyl-benzonitrile

This material which is known in the literature (CAS: 847943-59-3) wasmade as follows:

To a solution of 1-benzyloxy-4-bromo-2-tert-butyl-benzene (4.5 g) inanhydrous DMF (100 mL) were added Zn(CN)₂ (3.30 g), dppf (782 mg) and Zn(229 mg) under argon atmosphere and the reaction mixture was purged withargon for 10 minutes. Then, Pd₂(dba)₃ (645 mg) was added at 25° C. andthe reaction mixture was purged again with argon for 10 min. The mixturewas then stirred at 110° C. for 16 h. The mixture was cooled, filteredand the filtrate was evaporated under reduced pressure. The residue waspurified by column chromatography over silica gel (5-7% ethyl acetate inhexanes) to afford the title compound (3.2 g) as an off white solid. MS(m/z): 265.0 [M]⁺.

Step 3: 4-Benzyloxy-3-tert-butyl-benzoic acid

This material which is known in the literature (CAS: 146852-63-3) wasmade as follows:

To a solution of 4-benzyloxy-3-tert-butyl-benzonitrile (800 mg) in MeOH(30 mL) was added 6N aq. NaOH solution (40 mL) at 25° C. and thereaction mixture was refluxed for 16 h. The mixture was cooled to 25° C.and the solvent was evaporated under reduced pressure. The resultingresidue was diluted with water, acidified with conc. HCl and extractedwith EtOAc (2×50 ml). The combined organic layers were washed withbrine, dried over Na₂SO₄ and evaporated under reduced pressure to affordthe title compound (830 mg) as a brown solid. MS (m/z): 285.2 [M+H]⁺.

Step 4: 4-Benzyloxy-3-tert-butyl-benzoic acid methyl ester

This material which is known in the literature (CAS: 146852-62-2) wasmade as follows:

To a solution of 4-benzyloxy-3-tert-butyl-benzoic acid (830 mg) inanhydrous DMF (30 mL) at 25° C. were added Cs₂CO₃ (1.9 g) followediodomethane (0.273 mL) and the reaction mixture was stirred at 25° C.for 3 h. The reaction mixture was then filtered and the filtrate wasevaporated under reduced pressure. The residue was purified by columnchromatography over silica gel (gradient of 3-5% ethyl acetate inhexanes) to afford the title compound (740 mg) as an off white solid. MS(m/z): 299.3 [M+H]⁺.

Step 5: 5-(4-Benzyloxy-3-tert-butyl-phenyl)-3-methyl-[1,2,4]oxadiazole

To a solution of 4-benzyloxy-3-tert-butyl-benzoic acid methyl ester (740mg) and N-hydroxyacetamidine (229.7 mg) in anhydrous DMF (30 mL) wasadded NaH (218 mg) in portions at 25° C. and the reaction mixture wasstirred at 25° C. for 3 h. The mixture was then quenched with water andextracted with EtOAc (2×50 mL). The combined organic layers were washedwith brine, dried over Na₂SO₄, filtered and evaporated under reducedpressure. The residue was purified by column chromatography over silicagel (gradient of 7-10% EtOAc in hexane) to afford the title compound(650 mg) as an off white solid. MS (m/z): 323.0 [M+H]⁺.

Step 6: 2-tert-Butyl-4-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenol

To a solution of5-(4-benzyloxy-3-tert-butyl-phenyl)-3-methyl-[1,2,4]oxadiazole (300 mg)in anhydrous DCM (30 mL) kept at −78° C. was added BBr₃ (1M solution inDCM, 2.79 mL) and the reaction mixture was stirred at −78° C. for 2 h.The mixture was quenched with saturated aqueous NaHCO₃ solution (20 mL)and was extracted with DCM (2×30 mL). The combined organic layers werewashed with brine, dried over Na₂SO₄ and evaporated under reducedpressure. The residue was purified by column chromatography over silicagel (gradient of 5-20% EtOAc in hexanes) to afford the title compound(150 mg) as an off white solid. MS (m/z): 233.2 [M+H]⁺.

Intermediate A5:

2-tert-Butyl-4-[1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]phenol

Step 1: 2-(4-Benzyloxy-3-tert-butyl-phenyl)-4,5-dihydro-1H-imidazole

To a solution of 4-benzyloxy-3-tert-butyl-benzonitrile (1.4 g), obtainedin intermediate A1, Step 2, in ethylenediamine (20 mL) in a sealed tubewas added P₂S₅ (0.985 mg) at 25° C. and the reaction mixture was keptunder pressure with stirring at 120° C. for 2 h. The reaction mixturewas cooled to 25° C. and was then poured into water (100 mL). Themixture was stirred for 30 minutes and the resulting precipitate wascollected by filtration and dried in vacuo to afford the title compound(1.45 g) as an off white solid. MS (m/z): 308.9 [M+H]⁺.

Step 2: 2-(4-Benzyloxy-3-tert-butyl-phenyl)-1H-imidazole

To a solution of2-(4-benzyloxy-3-tert-butyl-phenyl)-4,5-dihydro-1H-imidazole (1.4 g) inDMSO (50 mL) were added potassium carbonate (690 mg) anddiacetoxy-iodobenzene (1.61 g) and the reaction mixture was stirred at25° C. for 16 h in the dark. The mixture was then diluted with water andwas extracted with dichloromethane (2×40 mL). The combined organiclayers were dried over Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified by column chromatography over amino silica gel(gradient of 33-40% EtOAc in hexanes) to afford the title compound (805mg) as an off white solid. MS (m/z): 306.8 [M+H]⁺.

Step 3:2-(4-Benzyloxy-3-tert-butyl-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole

To a suspension of NaH (16 mg) in anhydrous DMF (10 mL) at 0° C. wasadded a solution of 2-(4-benzyloxy-3-tert-butyl-phenyl)-1H-imidazole(500 mg) in anhydrous DMF (5 mL) and the reaction mixture was stirred at25° C. for 30 minutes. Then, SEM-chloride (0.087 ml) was added dropwiseat 25° C. and the reaction mixture was stirred at 25° C. for 2 h. Themixture was then quenched with water and was extracted with EtOAc (2×50mL). The combined organic layers were washed with brine, dried overNa₂SO₄ and evaporated in vacuo. The residue was purified by columnchromatography over silica gel (gradient of 30-40% ethyl acetate inhexanes) to afford the title compound (310 mg) as a sticky, colorlessliquid. MS (m/z): 436.9[M]⁺.

Step 4:2-tert-Butyl-4-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-phenol

A solution of2-(4-benzyloxy-3-tert-butyl-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole(300 mg) in MeOH (20 mL) was purged with argon for 10 min and thenPd(OH)₂ (100 mg) was added. An atmosphere of hydrogen was introduced andthe reaction mixture was stirred under H₂ at 25° C. for 6 h. The mixturewas filtered and the filtrate was evaporated in vacuo to afford thetitle compound (200 mg) as an off white solid. MS (m/z): 347.0 [M+H]⁺.

Intermediate A6

2-tert-Butyl-4-(1-methylimidazol-2-yl)phenol

Step 1: 2-(4-Benzyloxy-3-tert-butyl-phenyl)-1-methyl-1H-imidazole

A suspension of NaH (60% in mineral oil, 31 mg) in anhydrous THF (15 mL)was cooled to 0° C. and a solution of2-(4-benzyloxy-3-tert-butyl-phenyl)-1H-imidazole (200 mg), obtained inIntermediate A5, Step 2, in THF (20 mL) was then added at 0° C. Thereaction mixture was stirred at 0° C. for 30 min and then iodomethane(0.049 mL) was added at 0° C. Stirring was continued at 0° C. for 3 h.The mixture was quenched with water and was extracted with EtOAc (2×50mL). The combined organic layers were washed with brine, dried overNa₂SO₄, filtered and evaporated under reduced pressure. The residue waspurified by column chromatography over silica gel (gradient of 60-70% EAin hexanes) to afford the title compound (175 mg) as a sticky solid. MS(m/z): 320.8 [M+H]⁺.

Step 2: 2-tert-Butyl-4-(1-methylimidazol-2-yl)phenol

The title compound was obtained from2-(4-benzyloxy-3-tert-butyl-phenyl)-1-methyl-1H-imidazole in analogy toIntermediate 5, Step 4 as an off white solid. MS (m/z): 230.7 [M+H]⁺.

Intermediate A7

2-tert-Butyl-4-(1,3-oxazol-2-yl)phenol

Step 1: 2-(3-tert-Butyl-4-methoxymethoxy-phenyl)-oxazole

A solution of 4-bromo-2-tert-butyl-1-methoxymethoxy-benzene (500 mg,made from 4-bromo-2-tert-butyl-phenol according to WO2013079223) and2-tributylstannanyl-oxazole (0.92 mL) in anhydrous dioxane (10 mL) in asealed tube was purged with argon for 10 min. Then, PdCl₂(dppf)₂ CH₂Cl₂complex (149.5 mg) was added and the reaction mixture was purged againwith argon for 10 min. The mixture was then stirred at 100° C. for 4 hand was then cooled to 25° C. filtered and the filtrate was evaporatedunder reduced pressure. The residue was purified by columnchromatography over silica gel (gradient of 5-10% ethyl acetate inhexanes) to afford the title compound (350 mg) as a light brown liquid.MS (m/z): 262.8 [M+H]⁺.

Step 2: 2-tert-Butyl-4-oxazol-2-yl-phenol

To a solution of 2-(3-tert-buty-4-methoxymethoxy-phenyl)-oxazole (200mg) in anhydrous DCM (10 mL) at 0-5° C. was added 4N HCl in dioxane (2.5mL) and the reaction mixture was stirred at 25° C. for 28 h. The solventwas evaporated under reduced pressure and the residue was purified bycolumn chromatography over silica gel (gradient of 8-15% ethyl acetatein hexanes) to afford the title compound (120 mg) as an off white solid.MS (m/z): 217.9 [M+H]⁺.

Intermediate A8

2-tert-Butyl-4-morpholin-4-ylphenol

Step 1: 4-(3-tert-Butyl-4-methoxymethoxy-phenyl)-morpholine

To a solution of 4-bromo-2-tert-butyl-1-methoxymethoxy-benzene (900 mg,made from 4-bromo-2-tert-butyl-phenol according to WO2013079223) andmorpholine (0.44 mL) in anhydrous toluene (10 mL) in a sealed tube wereadded NaOtBu (475 mg) and xantphos (76.2 mg) at 25° C. The tube waspurged with argon for 10 min and then Pd₂(dba)₃ (60.3 mg) was added andthe tube was again purged with argon for 10 min. Then, the mixture wasstirred under pressure for 16 at 110° C. and was then cooled to 25° C.and filtered. The filtrate was evaporated under reduced pressure and theresulting crude material was purified by column chromatography (gradientof 7-10% ethyl acetate in hexanes) to afford the title compound (560 mg)as a sticky liquid. ¹H-NMR (400 MHz, δ, CDCl₃): 1.38 (s, 9H), 3.04-3.10(m, 4H), 3.48 (s, 3H), 3.80-3.90 (m, 4H), 5.17 (s, 2H), 6.69 (dd, 1H),6.93 (d, 1H), 7.04 (d, 1H).

Step 2: 2-tert-Butyl-4-morpholin-4-yl-phenol

The title compound was obtained from4-(3-tert-butyl-4-methoxymethoxy-phenyl)-morpholine using the conditionsdescribed in Intermediate A7, Step 2, as an off white solid. MS (m/z):235.9 [M+H]⁺.

Intermediate A9

2-tert-Butyl-4-(1-methyl-1H-imidazol-2-yl)-phenol

To a solution of 4-bromo-2-tert-butyl-phenol (CAS: 10323-39-4, 200 mg)and1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-imidazole(272 mg) in anhydrous DMF (10 mL) was added K₂CO₃ (362 mg) at 25° C.under a nitrogen atmosphere. The reaction mixture was purged with argonfor 10 min, and then PdCl₂(dppf)₂ DCM complex (14.2 mg) was added. Thevessel was again purged with argon for 10 min and the reaction mixturewas stirred at 120° C. for 28 h. The mixture was cooled to 25° C.,filtered and the filtrate was evaporated under reduced pressure. Theresidue was purified by column chromatography over silica gel (gradientof 2-5% MeOH in DCM) to afford the title compound (124 mg) as a brownsolid. MS (m/z): 230.9 [M+H]⁺.

Intermediate A10

2-ter-butyl-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenol

Step 1: 3-tert-Butyl-4-hydroxy-benzoic acid methyl ester

To a solution of 3-tert-butyl-4-hydroxy-benzoic acid (CAS: 66737-88-0, 3g) in anhydrous MeOH (40 mL) was added dropwise conc. H₂SO₄ (0.4 mL) at25° C. and the reaction mixture was stirred at reflux for 16 h. Then,the solvent was evaporated under reduced pressure. The residue wasdiluted with DCM (50 mL) and the solution was washed with water andbrine, dried over Na₂SO₄ and filtered. The filtrate was evaporated underreduced pressure and the residue was purified by column chromatographyover silica gel (gradient of 0.5-1% MeOH in DCM) to afford the titlecompound (2.8 g) as an off white solid. MS (m/z): 209.4 [M+H]⁺.

Step 2: 3-tert-Butyl-4-hydroxy-benzoic acid hydrazide

To a solution of 3-tert-butyl-4-hydroxy-benzoic acid methyl ester (3.7g) in anhydrous MeOH (40 mL) in a sealed tube was added hydrazinehydrate (4.36 mL) at 25° C. and the reaction mixture was heated underpressure at to 65° C. for 16 h. The mixture was then cooled to 25° C.and the solvent was evaporated under reduced pressure. The residue waspurified by column chromatography over silica gel (gradient of 2-4% MeOHin DCM) to afford the title compound (2.8 g, 75%) as off white solid. MS(m/z): 209.1 [M+H]⁺.

Step 3: 2-tert-butyl-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenol

To a suspension of 3-tert-butyl-4-hydroxy-benzoic acid hydrazide (1.5 g)in triethyl orthoacetate (25 mL) was heated to reflux at 150° C. for 7h. The reaction mixture was then cooled to 25° C. and the solvent wasevaporated under reduced pressure. The residue was diluted with DCM (50mL) and was washed with water and brine. The organic layer was driedover Na₂SO₄, filtered, and evaporated under reduced pressure. The crudematerial was purified by column chromatography over silica gel (gradientof 2-3% MeOH in DCM) to afford the title compound (1.15 g) as an offwhite solid. MS: 233.1 [M+H]⁺.

Intermediate A14:

4-Chloro-2-cyclopropyl-5-methylsulfonylphenol

Step 1: 1-Bromo-2-chloro-5-fluoro-4-nitrobenzene

To a stirred solution of 2-bromo-1-chloro-4-fluorobenzene (CAS:201849-15-2; 10 g) in sulfuric acid (95-97%; 100 mL) was gradually addedpotassium nitrate (5.82 g) at −5° C. The reaction mixture was stirred at−5° C. for 1.5 hours and was then poured on 400 mL ice-water. Theprecipitate was filtered and dried in vacuo to provide the titlecompound as a colorless solid (11.54 g). MS (m/z): 253 [M]⁺.

Step 2: 1-Bromo-2-chloro-5-methoxy-4-nitrobenzene

To a solution of 1-bromo-2-chloro-5-fluoro-4-nitrobenzene (11.0 g) inmethanol (110 mL) was slowly added sodium methoxide (2.45 g) at 0° C.and the reaction mixture was stirred at 0° C. for 1.5 hours. Thesuspension was poured on water and was extracted with EtOAc. Thecombined organic extracts were dried with MgSO₄, filtered andconcentrated in vacuo to provide the title compound as a yellow solid(11.2 g). MS (m/z): 265[M]⁺.

Step 3: 1-Chloro-4-methoxy-2-methylsulfonyl-5-nitrobenzene

To a solution of L-proline (61.3 mg) in DMSO (2 mL) was added sodiumhydroxide (24.0 mg) and the mixture was stirred at rt for 30 minutes.Copper(I)iodide (114 mg), 1-bromo-2-chloro-5-methoxy-4-nitrobenzene(0.20 g) and sodium methanesulfinate (173 mg) were added. The reactionmixture was heated to 60° C. to give a turbid blue solution. After 5hours, the reaction was allowed to cool down to room temperature. Themixture was poured on 50 mL 10% aqueous NaHCO₃ solution and 50 mL EtOAcand the layers were filtered to remove any precipitates. The filtratedlayers were then separated. The aqueous layer was extracted a secondtime with 50 mL EtOAc and the organic layers were washed with 50 mLbrine, dried over MgSO₄, filtered and concentrated in vacuo to give thetitle compound as a yellow solid (122 mg). MS (m/z): 265 [M]⁺.

Step 4: 5-Chloro-2-methoxy-4-methylsulfonylaniline

To a mixture of ethanol (2.00 mL) and water (2.00 mL) was added aceticacid (140 μL) and this mixture was stirred under reflux for 10 minutes.To the solution thus obtained was added iron (163 mg) and1-chloro-4-methoxy-2-methylsulfonyl-5-nitrobenzene (200 mg) and themixture was stirred for additional 20 minutes. After cooling, 20 mL ofacetone was added and the iron was filtered off through a pad ofdicalite and washed with 20 mL of acetone. The filtrate was concentratedin vacuo and the residue was purified by silica gel chromatography,eluting with a gradient of n-heptane in ethyl acetate (100/0 to 50/50).This provided the title compound as white crystals (177 mg). MS (m/z):235 [M]⁺.

Step 5: 1-Chloro-5-iodo-4-methoxy-2-methylsulfonylbenzene

To a suspension of 5-chloro-2-methoxy-4-methylsulfonylaniline (1.50 g)in semi-concentrated HCl (18.5%, 15.1 g) was added dropwise at 0-5° C. asolution of sodium nitrite (461 mg) in water (3.66 mL). The initialsuspension gradually cleared and turned nearly into a solution. Thismixture was stirred for 1 hour at 0° C. and was then added dropwise to astirred suspension of potassium iodide (3.17 g) in aq. HBr (48%, 21.0mL) at rt. Stirring was continued for 30 minutes at rt. The reactionmixture was poured on 100 mL 2M aqueous Na₂CO₃ solution and 50 mL EtOAcand the layers were separated. The aqueous layer was extracted and asecond time with 100 mL EtOAc. The organic layers were washed withNa₂S₂O₃ and brine (50 mL), dried over MgSO₄, filtered and concentratedin vacuo. The residue was purified by silica gel chromatography, elutingwith a gradient of n-heptane in ethyl acetate (100/0 to 50/50) toprovide the title compound as a light yellow solid (950 mg). MS (m/z):346 [M]⁺.

Step 6: 4-Chloro-2-iodo-5-methylsulfonylphenol

To a solution of 1-chloro-5-iodo-4-methoxy-2-methylsulfonylbenzene (750mg) in AcOH (15.6 g) was added aqueous HBr (48%, 4.7 ml) and the clear,colorless solution was stirred at reflux for 4 days in a sealed tube.The reaction mixture was cooled, poured on 100 mL water and 100 mL EtOAcand the layers were separated. The aqueous layer was extracted a secondtime with 100 mL EtOAc. The organic layers were washed with 100 mLbrine, dried over MgSO₄, filtered and concentrated in vacuo. Thecompound was purified by silica gel chromatography, eluting with agradient of n-heptane in ethyl acetate (100/0 to 60/40) to give thetitle compound as a light yellow solid (625 mg). MS (m/z): 330.87[M−H]⁻.

Step 7: 4-Chloro-2-cyclopropyl-5-methylsulfonylphenol

To a suspension of 4-chloro-2-iodo-5-methylsulfonylphenol (200 mg) intoluene (3 mL) were added under argon potassiumcyclopropyltrifluoroborate (178 mg), water (0.21 mL), cesium carbonate(490 mg), palladium (II) acetate (6.75 mg) andbutyldi-1-adamantylphosphine (21.6 mg) and the mixture was stirred in asealed tube at 125° C. for 66 hours. The reaction mixture was cooled andpoured on sat. aqueous NH₄Cl solution and ethyl acetate and the layerswere separated. The aqueous layer was extracted twice with additionalethyl acetate. The organic layers were dried over MgSO₄, filtered,treated with silica gel and evaporated. The compound was purified bysilica gel chromatography, eluting with a gradient of n-heptane in ethylacetate (100/0 to 50/50) to provide the title compound as a colorlesssolid (72 mg). MS (m/z): 245 [M]⁺.

Intermediate A15:

2-tert-Butyl-4-methylsulfonylphenol

Step 1: 4-Bromo-2-tert-butyl-1-phenylmethoxybenzene

To a solution of 4-bromo-2-tert-butylphenol (CAS: 10323-39-4; 500 mg) inDMF (5 mL) was added NaH (114 mg) and the reaction mixture was stirredfor 10 minutes at rt. Then, benzylchloride (290 mg) was added and thereaction mixture was stirred for 2 hours at rt. The mixture was pouredon 30 mL 10% aqueous NH₄Cl solution and 30 mL EtOAc and the layers wereseparated. The aqueous layer was extracted a second time with 30 mLEtOAc. The organic layers were washed with 30 mL brine, dried overMgSO₄, filtered and concentrated in vacuo. The residue was purified bysilica gel chromatography eluting with a gradient of n-heptane in ethylacetate (100/0 to 80/20) to give the title compound as a colorless solid(583 mg. MS (m/z): 318 [M]⁺.

Step 2: 2-tert-Butyl-4-methylsulfonyl-1-phenylmethoxybenzene

To a solution of L-proline (88.3 mg) in DMSO (10 mL) was added sodiumhydroxide (34.6 mg) and the mixture was stirred at room temperature for30 minutes. Copper(I)iodide (165 mg),4-bromo-2-tert-butyl-1-phenylmethoxybenzene (345 mg) and sodiummethanesulfinate (249 mg) were added. The reaction mixture was heated to60° C. to give a turbid blue solution and then the reaction was stirredfor 2 hours at 60° C. TLC and LC-MS showed no conversion. Again, sodiummethanesulfinate (249 mg) was added and the reaction mixture was stirredfor 2 hours at 60° C. TLC and LS-MS showed again no conversion. Thereaction mixture was transferred into a sealed tube and stirred at 135°C. over night. TLC and LC-MS showed complete conversion and LC-MS showedthe presence of the desired mass. The reaction mixture was poured on 50mL 10% aqueous NH₄Cl solution and 50 mL EtOAc and the layers wereseparated. The aqueous layer was extracted a second time with 50 mLEtOAc. The organic layers were washed with brine (50 mL), dried overMgSO₄, filtered and concentrated in vacuo. The compound was purified bysilica gel chromatography, eluting with a gradient of n-heptane in ethylacetate (100/0 to 60/40) to provide the title compound as a colorlesssolid (278 mg). MS (m/z): 317.12 [M−H]⁻.

Step 3: 2-tert-Butyl-4-methylsulfonylphenol

To a solution of 2-tert-butyl-4-methylsulfonyl-1-phenylmethoxybenzene(250 mg) in MeOH (3 mL) and ethyl acetate (3 mL) was added Pd oncharcoal (10% Pd, 25 mg) under an argon atmosphere. The reaction wasevacuated and purged with hydrogen. The reaction was stirred for 18hours at 1.7 bar under H₂-atmosphere. The reaction mixture was thenfiltered through a filter aid (dicalite) and the filtrate wasconcentrated in vacuo. The residue was purified by silica gelchromatography, eluting with a gradient of n-heptane in ethyl acetate(100/0 to 50/50) to provide the title compound as colorless solid (140mg). MS (m/z): 227.08 [M−H]⁻.

Intermediate A16:

5-tert-Butyl-4-hydroxy-2-methylbenzonitrile

To a solution of 4-bromo-2-tert-butyl-5-methylphenol (CAS: 51345-97-2,0.45 g), made from 4-bromo-3-methylphenol according to WO2005058798 orWO2008059026, in DMF (4 mL) under argon were added water (40 μL),1,1′-bis(diphenylphosphino)ferrocene (30.8 mg), zinc cyanide (120 mg),zinc (4.84 mg), zinc acetate (13.6 mg) andtris(dibenzylideneacetone)-dipalladium (0) (16.9 mg). The reactionmixture was capped and heated in a microwave oven for 30 minutes at 180°C. The reaction mixture was then poured into saturated aqueous NH₄Clsolution containing a small volume of water, and ethyl acetate, and thelayers were separated. The aqueous layer was extracted twice with ethylacetate. The organic layers were dried over MgSO₄, filtered, treatedwith silica gel and evaporated. The compound was purified by silica gelchromatography eluting with a gradient of n-heptane in ethyl acetate(100/0 to 75/25) to give the title compound (160 mg) as a light brownsolid. MS (m/z): 188.11 [M−H]⁻.

Intermediate A17:

4-tert-butyl-5-hydroxy-2-methylbenzonitrile

This material was made in analogy to Intermediate A16 from5-bromo-2-tert-butyl-4-methylphenol (CAS 1237614-78-6), made from3-bromo-4-methylphenol according to WO2005058798 or WO2008059026), as alight yellow solid. MS (m/z): 188.11 [M−H]⁻.

Intermediate A18:

2-ter-Butyl-4-[3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazol-4-yl]-phenol

Step 1: 144-Benzyloxy-3-tert-butyl-phenyl)-ethanone

To a solution of 1-benzyloxy-4-bromo-2-tert-butyl-benzene (IntermediateA15, Step 1, 5.0 g) in DMF (40 mL) and water (4 mL) were addedn-butylvinylether (8.1 mL), 1.3-bis(diphenylphosphino)propane (1.61 g),K₂CO₃ (2.60 g) and Pd(OAc)₂ (351 mg) at 25° C. Then, the mixture waspurged with argon and was stirred at 150° C. for 5 h. The mixture wascooled to 25° C., diluted with aq 2N HCl (25 mL) and stirred at 25° C.for 2 h. The mixture was extracted with EtOAc (2×100 mL) and thecombined organic layers were washed with sat aq. NaHCO₃ solution. Theorganic layer was dried over Na₂SO₄, filtered and evaporated underreduced pressure. The residue was purified by column chromatography oversilica gel (5% ethyl acetate in hexanes) to afford the title compound(1.6 g) as a brown liquid. MS (m/z): 283.2 [M+H]⁺.

Step 2: 1-(4-Benzyloxy-3-tert-butyl-phenyl)-2-bromo-ethanone

To a solution of 1-(4-benzyloxy-3-tert-butyl-phenyl)-ethanone (1.0 g) inanhydrous THF (20 mL) and MeOH (10 mL) was added a solution of Bu₄NBr₃(1.71 g) in THF (10 mL) at 25° C. and the reaction mixture was stirredat 50° C. for 5 h. The mixture was cooled to 25° C. and the solvent wasevaporated under reduced pressure. The residue was purified by columnchromatography over silica gel (5% ethyl acetate in hexane) to affordthe title compound (800 mg) as colorless liquid that was used withoutfurther characterization.

Step 3: 5-(4-Benzyloxy-3-tert-butyl-phenyl)-1H-imidazole

A solution of 1-(4-benzyloxy-3-tert-butyl-phenyl)-2-bromo-ethanone (800mg) in formamide (30 mL) was stirred at 160-170° C. for 4 h. Thereaction mixture was then cooled to 25° C. and was diluted with EtOAc(30 mL) and water (30 mL). The organic layer was separated and theaqueous layer was extracted with more EtOAc (2×30 mL). The combinedorganic layers were dried over Na₂SO₄, filtered and evaporated underreduced pressure. The residue was purified by column chromatography overamine silica gel (gradient of 5-10% MeOH in DCM) to afford the titlecompound (330 mg) as light yellow solid. MS (m/z): 306.9 [M+H]⁺.

Step 4:5-(4-Benzyloxy-3-tert-butyl-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole

To a suspension of NaH (51 mg) in anhydrous THF (20 mL) was addeddropwise a solution of 5-(4-benzyloxy-3-tert-butyl-phenyl)-1H-imidazole(330 mg) in anhydrous THF (10 mL) at 25° C. The reaction mixture wasstirred at 25° C. for 30 min and then(2-chloromethoxy-ethyl)-trimethyl-silane (0.287 ml) was added dropwiseat 25° C. The reaction mixture was stirred at 25° C. for 3 h, was thenquenched with water and was extracted with EtOAc (2×50 mL). The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered andevaporated under reduced pressure. The residue was purified by columnchromatography over silica gel (40% ethyl acetate in hexanes) to get thetitle compound (310 mg) as an off white solid. MS (m/z): 436.9 [M+H]⁺.

Step 5:2-tert-Butyl-4-[3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazol-4-yl]-phenol

To a solution of5-(4-benzyloxy-3-tert-butyl-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole(170 mg) in MeOH (20 mL) was purged with argon for 10 min and thenPd(OH)₂ (100 mg) was added at 25° C. The reaction mixture was stirred at25° C. for 4 h under a H₂ atmosphere. The mixture was then filtered andthe filtrate was evaporated under reduced pressure to afford the titlecompound (170 mg) as an off white solid. MS (m/z): 347.0 [M+H]⁺.

Intermediate A19

4-chloro-2-cyclopropyl-5-methylphenol

Step 1: 5-Chloro-2-methoxy-4-methyl-phenylamine

To a solution of 1-chloro-4-methoxy-2-methyl-5-nitro-benzene (CAS:101080-03-9, 10.64 g) in MeOH (250 mL) and water (125 mL) were added Zndust (24.15 g) and NH₄Cl (31.05 g) at 25° C. and the reaction mixturewas stirred for 2 h at 25° C. The mixture was filtered through a celitepad and the filtrate was evaporated, diluted with DCM (300 mL) andwashed with water (2×200 mL). The organic layer was dried over Na₂SO₄,filtered and evaporated to provide the title compound (8.99 g) as alight brown solid. ¹H NMR (400 MHz, CDCl₃): 2.25 (3H, s), 3.80 (3H, s),6.60 (1H, s), 6.68 (1H, s).

Step 2: 1-Chloro-5-iodo-4-methoxy-2-methyl-benzene

To a suspension of 5-chloro-2-methoxy-4-methyl-phenylamine (8.98 g) inconc. HCl (37%, 84 mL) was added a solution of NaNO₂ (7.22 g) in water(70 mL) at 0° C. After stirring the reaction mixture for 30 min at 0°C., a solution of KI (34.74 g) in water (176 mL) was added and thereaction mixture was then stirred at 25° C. for 16 h. The reactionmixture was diluted with ethyl acetate (250 mL) and the organic layerwas separated, washed with water (100 mL), saturated sodium thiosulfatesolution (100 mL) and brine (50 mL). The organic layer was dried overNa₂SO₄, filtered and evaporated to get a crude material which waspurified by flash chromatography over silica gel (hexanes) to afford thetitle compound (11.9 g) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ:2.32 (3H, s), 3.84 (3H, s), 6.65 (1H, s), 7.68 (1H, s).

Step 3: 4-Chloro-2-iodo-5-methyl-phenol

To a stirred solution of 1-chloro-5-iodo-4-methoxy-2-methyl-benzene(3.13 g) in anhydrous DCM (20 mL) at 0° C. was added a solution of 1Mboron tribromide in DCM (44.4 ml) and the resulting solution was stirredfor 2 h at 25° C. The reaction mixture was quenched with saturatedaqueous sodium bicarbonate solution and was diluted with DCM (20 mL).The organic layer was separated and washed with water (25 mL) and brine(25 mL). The organic layer was dried over Na₂SO₄, filtered andevaporated under reduced pressure. The residue was purified by flashsilica gel chromatography (gradient of 5-10% ethyl acetate in hexanes)to afford the title compound as a brown solid (2.89 g). ¹H NMR (400 MHz,CDCl₃) δ: 2.30 (3H, s), 5.12 (1H, s), 6.86 (1H, s), 7.57 (1H, s).

Step 4: 4-Chloro-2-cyclopropyl-5-methyl-phenol

To a solution of 4-chloro-2-iodo-5-methyl-phenol (500 mg) in toluene(8.5 mL) and water (0.5 mL) were added cyclopropylboronic acid (416 mg),K₃PO₄ (1.31 g), Pd(OAc)₂ (33 mg) and tricyclohexylphosphine (94 mg) andthe reaction mixture was heated at 100° C. for 16 h. The mixture wasfiltered through celite and the filtrate was washed with brine. Theorganic layer was dried over Na₂SO₄ and was vaporated in vacuo. Theresidue was purified by flash chromatography over silica gel (gradientof 2-5% ethyl acetate in hexanes) to afford the title compound (210 mg)as a brown liquid. ¹H NMR (400 MHz, CDCl₃): 0.59-0.62 (2H, m), 0.92-0.96(2H, m), 1.69-1.76 (1H, m), 5.29 (1H, s), 6.86 (1H, s), 7.57 (1H, s).

Intermediates A19A and A19B

The following Intermediates were synthesized from4-chloro-2-iodo-5-methyl-phenol and the suitable boronate building blockin analogy to Intermediate A19, Step 4:

Intermediate Systematic Name Building block Analytics A19A

cyclohexene-1-boronic acid pinacol ester Rƒ. 0.4 (10% ethyl acetate inhexanes) A19B

3,5-dihydro-2H-pyran- 4-boronic acid pinacol ester ¹H NMR (400 MHz,CDCl₃): 2.29 (3H, s), 2.38-2.40 (2H, m), 3.92 (2H, t, J = 4), 4.28-4.29(2H, m), 5.33 (1H, s), 5.92 (1H, s) 6.77 (1H, s), 7.05 (1H, s).Intermediate A20:

4-Chloro-2-cyclohexyl-5-methyl-phenol

To a solution of 4-chloro-2-cyclohex-1-enyl-5-methyl-phenol(Intermediate A19A, 202 mg) in methanol (10 mL) was added Pd on carbon(10% Pd, 25 mg) and the reaction mixture was stirred at 25° C. underhydrogen atmosphere for 45 min. The mixture was then filtered throughcelite and the filtrate was evaporated under reduced pressure to affordthe title compound (190 mg) as a colorless liquid. R_(f)=0.3 (10% ethylacetate in hexane) The following Intermediate was synthesized from thecorresponding precursor in analogy to Intermediate A20:

Intermediate Systematic Name Building block Analytics A21

4-Chloro-2-(3,6- dihydro-2H-pyran-4- yl)-5-methyl-phenol IntermediateA19B ¹H NMR (400 MHz, CDCl₃): 1.72-1.78 (4H, m), 2.27 (3H, s), 3.01-3.05 (1H, m), 3.51-3.57 (2H, m), 4.05-4.07 (2H, m), 5.33 (1H, s), 4.73(1H, s) 6.60 (1H, s), 7.09 (1H, s).Intermediate A22

2-Chloro-4-cyclopropyl-5-hydroxy-benzonitrile

Step 1: 5-Amino-2-bromo-4-chloro-phenol

To a solution of 4-bromo-2-chloro-5-methoxy-phenylamine (CAS:98446-54-9, 2.05 g) in anhydrous DCM (40 mL) at 0° C. was added asolution of BBr₃ in DCM (1M, 86.7 mL) and the reaction mixture wasstirred at 25° C. for 12 h. The mixture was quenched with saturatedaqueous NaHCO₃ solution (40 mL) and was extracted with DCM (2×60 mL).The combined organic layers were dried over Na₂SO₄ and were evaporatedunder reduced pressure to afford the title compound (1.9 g) as a brownsolid. ¹H NMR (400 MHz, DMSO-D6): 5.36 (2H, s), 6.41 (1H, s), 7.21 (1H,s), 9.94 (1H, s).

Step 2: Carbonic acid 2-bromo-5-(ditert-butoxycarbonyl)amino-4-chloro-phenyl ester tert-butyl ester

To a stirred solution of 5-amino-2-bromo-4-chloro-phenol (1.9 g) inanhydrous THF (40 mL) at 25° C. were added di-tert-butyldicarbonate(“Boc anhydride”, 10.96 mL), Et₃N (7.12 mL) and DMAP (10 mg) and thereaction mixture was refluxed for 12 h. The solvent was evaporated underreduced pressure and the residue was purified by flash chromatographyover silica gel (gradient of 2-5% ethyl acetate/in hexanes) to affordthe desired compound (3.82 g) as a white solid. MS (m/z): 522.1 [M]⁺.

Step 3: Carbonic acid 5-(ditert-butoxycarbonyl)amino-4-chloro-2-cyclopropyl-phenyl ester tert-butylester

The title compound was obtained in analogy to intermediate A19, Step 4,from carbonic acid 2-bromo-5-(ditert-butoxycarbonyl)amino-4-chloro-phenyl ester tert-butyl ester andcyclopropylboronic acid as a colorless, sticky liquid. MS (m/z): 484.0[M]⁺.

Step 4: 5-Amino-4-chloro-2-cyclopropyl-phenol

To a solution of carbonic acid 5-(ditert-butoxycarbonyl)amino-4-chloro-2-cyclopropyl-phenyl ester tert-butylester (1.05 g) in DCM (20 mL) was added TFA (6.45 mL) and the reactionmixture was stirred at 25° C. for 2 h. The solvent was evaporated underreduced pressure and the residue was diluted with DCM (50 mL). Thesolution was washed with saturated aqueous NaHCO₃ solution (30 mL) andwater (20 mL). The organic layer was dried over anhydrous Na₂SO₄,filtered and evaporated to afford the title compound (397 mg) as a brownsolid. ¹H NMR (400 MHz, DMSO-D₆) δ: 0.42-0.46 (2H, m), 0.70-0.74 (2H,m), 1.80-1.87 (1H, m), 4.94 (2H, s), 6.26 (1H, s), 6.51 (1H, s), 9.11(1H, s).

Step 5: 4-Chloro-2-cyclopropyl-5-iodo-phenol

To a suspension of 5-amino-4-chloro-2-cyclopropyl-phenol (395 mg) inwater (1 mL) at 0° C. was added slowly conc. H₂SO₄ (1.29 mL), followedby a solution of NaNO₂ (148 mg) in water (5.5 mL) at 0° C. Afterstirring the reaction mixture for 10 more minutes, a solution of KI (714mg) in water (1 mL) was added and reaction mixture was heated at 60° C.for 2 h. The mixture was cooled to 25° C. and extracted with DCM (2×30mL). The combined organic extracts were dried over Na₂SO₄, filtered andevaporated. The residue was purified by flash chromatography over silicagel (gradient of 2-5% ethyl acetate in hexanes) to afford the titlecompound (241 mg) as a yellow liquid. MS (m/z): 292.8 [M−H]⁻.

Step 6: 2-Chloro-4-cyclopropyl-5-hydroxy-benzonitrile

To a solution of 4-chloro-2-cyclopropyl-5-iodo-phenol (238 mg) inanhydrous DMF (5 mL) was added CuCN (145 mg) and the reaction mixturewas heated at 100° C. for 24 h. The solvent was evaporated in vacuo andthe residue was purified by flash chromatography over silica gel(gradient of 5-10% ethyl acetate in hexanes) to afford the titlecompound (120 mg) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): 0.68-0.72(2H, m), 1.06-1.10 (2H, m), 1.86-1.89 (1H, m), 5.64 (1H, s), 7.09 (1H,s), 7.10 (1H, s).

Intermediate A23

N-(2-Chloro-4-cyclopropyl-5-hydroxy-phenyl)-methanesulfonamide

To a solution of 5-amino-4-chloro-2-cyclopropyl-phenol (78 mg), obtainedin Intermediate A22, Step 4, in DCM (5 mL) were added pyridine (0.04 mL)and methanesulfonyl chloride (0.03 mL) at 0° C. and the reaction mixturewas then stirred at 25° C. for 12 h. The mixture was quenched with 6Naqueous NaOH solution (5 mL) and water (10 mL). The organic layer wasseparated and the aqueous phase was extracted with additional DCM (20mL). The aqueous layer was cooled to 0° C., acidified with conc. HCl andextracted with ethyl acetate (2×20 mL). The combined organic ethylacetate extracts were washed with brine, dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by flashchromatography over silica gel (gradient of 5-20% ethyl acetate inhexanes) to provide the title compound (58 mg) as a brown solid. ¹H NMR(400 MHz, DMSO-D): 0.62-0.65 (2H, m), 0.84-0.89 (2H, m), 1.97-2.05 (1H,m), 2.95 (3H, s), 6.80 (1H, s), 6.91 (1H, s), 9.19 (1H, s), 9.80 (1H,s).

Intermediate A24:

4-tert-Butyl-3-hydroxy-benzonitrile

Step 1: 4-tert-Butyl-3-methoxy-benzamide

A solution of 4-tert-butyl-3-methoxy-benzoic acid (CAS: 79822-46-1: 2 g)in SOCl₂ (5 mL) was refluxed for 2 h. Excess SOCl₂ was evaporated invacuo and the residue was dissolved in THF (5 mL) and conc. aqueous NH₃solution (2 mL) was added dropwise at 0° C. The reaction mixture wasstirred at rt for 1 h and was then extracted with ethyl acetate (2×20mL). The combined organic extracts were dried over Na₂SO₄ and wereevaporated under reduced pressure to afford the title compound (1.95 g)as a white solid. ¹H NMR (400 MHz, CDCl₃): 1.36 (9H, s), 3.88 (3H, s),6.0 (2H, bs), 7.20 (1H, dd, J=4 Hz, 12 Hz), 7.30 (I H, d, J=12 Hz), 7.42(1H, d, J=4 Hz).

Step 2: 4-tert-Butyl-3-methoxy-benzonitrile

A solution of 4-tert-butyl-3-methoxy-benzamide (500 mg, 2.41 mmol) inPOCl₁₃ (5 mL) was refluxed for 6 h. Excess POCl₁₃ was evaporated invacuo and the residue was dissolved in ethyl acetate (30 mL) and washedwith saturated aqueous NaHCO₃ solution (25 mL). The organic layer wasdried over Na₂SO₄, filtered, and was then evaporated under reducedpressure. The crude material was purified by flash chromatography oversilica gel (5% ethyl acetate in hexane) to provide the title compound(360 mg) as a colorless liquid. MS (M/z): 189.0 [M]⁺.

Step 3: 4-tert-Butyl-3-hydroxy-benzonitrile

The title compound was obtained in analogy to intermediate A22, Step 1,from 4-tert-butyl-3-methoxy-benzonitrile by treatment with BBr₃ as ayellow oil. ¹H NMR (400 MHz, CDCl₃): 1.39 (9H, s), 5.41 (1H, s), 6.93(1H, d, J=4 Hz), 7.17 (1H, dd, J=4 Hz, 12 Hz), 7.33 (1H, d, J=8 Hz).

The following Intermediate was synthesized from the correspondingprecursor in analogy to Intermediate A24, Step 3:

Intermediate Systematic Name Building block Analytics A25

4-tert-butyl-3- methoxybenzamide Intermediate A24, Step 1 ¹H NMR (400MHz, CDCl₃): 1.55 (9H, s), 5.73 (1H, s), 7.16 (1H, dd, J = 4 Hz, 12 Hz),7.30 (1H, d, J = 12 Hz), 7.34 (1H, d, J = 4 Hz).Intermediate A30:

6-Cyclopropyl-2-methylbenzo[d]thiazol-5-ol

Step 1: 6-Iodo-5-methoxy-2-methylbenzo[d]thiazole

A solution of 5-methoxy-2-methylbenzo[d]thiazol-6-amine (CAS:89976-71-6; 1.0 g) in water (2.6 mL) and conc. hydrochloric acid (2.54mL) was cooled down to 0° C. Then, a solution of sodium nitrite (373 mg)in water (2.6 mL) was added dropwise over 3 minutes. The brown solutionwas stirred at 0° C. for 5 minutes and was then added dropwise to avigorously stirred suspension of potassium iodide (2.56 g) in HBrsolution (48% in water, 12.2 mL) over 5 minutes at rt. Stirring at rtwas continued for 20 minutes. The reaction mixture was poured into 2Maqueous Na₂CO₃ solution (60 mL) and ethyl acetate (50 mL) and the layerswere separated. The aqueous layer was extracted twice with ethyl acetate(30 mL, each). The organic layers were washed once with aqueous Na₂S₂O₃solution (50 mL) and once with brine (20 mL), dried over MgSO₄,filtered, treated with silica gel and evaporated. The compound waspurified twice by silica gel chromatography on a 50 g column using anMPLC system eluting with a gradient of n-heptane/ethyl acetate (1000 to50/50) to provide the title compound as a slightly impure, light brownsolid (0.66 g). MS (m/z): 306.4 [M+H]⁺.

Step 2: 6-Iodo-2-methylbenzo[d]thiazol-5-ol

To a solution of 6-iodo-5-methoxy-2-methylbenzo[d]thiazole (0.625 g) indichloromethane (4 mL) in a sealed tube under argon at room temperaturewas added dropwise tribromoborane (1M in DCM: 2.25 mL) and the lightbrown suspension was stirred at reflux (oil bath at 60° C.) for 1.5hours. No product was detected at this point. More DCM (4.00 mL) andtribromoborane (1M in dichloromethane; 2.25 mL) were added after 3 hoursand stirring was continued at 60° C. over the weekend. The reactionmixture was poured into water and DCM (containing a small volume ofmethanol) and the layers were separated. The aqueous layer was extractedtwice with DCM. The organic layers were washed once with brine, driedover MgSO₄, filtered and evaporated. The residue was taken up in ethylacetate and dichloromethane and was partially evaporated until asuspension formed. This suspension was filtered, washed with a smallamount of ethyl acetate and dried in vacuo to provide the title compoundas a light brown solid (455 mg). MS (m/z): 292.3 [M+H]⁺.

Step 3: 6-cyclopropyl-2-methyl-1,3-benzothiazol-5-ol

To a suspension of 6-iodo-2-methylbenzo[d]thiazol-5-ol (0.15 g) intoluene (3 mL) were added under argon potassiumcyclopropyltrifluoroborate (152 mg), water (0.21 mL), cesium carbonate(420 mg), palladium (1) acetate (5.78 mg) andbutyldi-1-adamantylphosphine (18.5 mg) and the mixture was stirred in asealed tube at 125° C. for 66 hours. The reaction mixture was pouredinto saturated aqueous NH₄Cl solution and ethyl acetate and the layerswere separated. The aqueous layer was extracted twice with ethylacetate. The organic layers were combined, dried over MgSO₄, filtered,treated with silica gel and evaporated. The compound was purified bysilica gel chromatography on a 10 g column using an MPLC system elutingwith a gradient of n-heptane in ethyl acetate (100/0 to 0/100) toprovide the title compound as alight brown solid. MS (m/z): 206.06[M+H]⁺.

According to LC-MS, the material contains some2-methylbenzo[d]thiazol-5-ol as an impurity.

Intermediate A31

4-Chloro-2-cyclobutyl-5-methyl-phenol

Step 1: 1-(5-Chloro-2-methoxy-4-methyl-phenyl)-cyclobutanol

To a solution of 1-chloro-5-iodo-4-methoxy-2-methyl-benzene (1 g).Intermediate A19, Step 2, in anhydrous THF (20 mL) was added dropwiseisopropyl magnesium chloride (2M in THF, 2.12 mL) at −40° C. under anitrogen atmosphere and the reaction mixture was stirred at −40° C. for1 h. Then, a solution of cyclobutanone (298 mg) in anhydrous THF (3 mL)was added dropwise to the reaction mixture at −40° C. and stirring wascontinued at 25° C. for 11 h. The reaction mixture was quenched withsaturated aqueous NH₄Cl solution and was extracted with ethyl acetate(2×30 mL). The combined organic layers were dried over Na₂SO₄, filtered,and evaporated under reduced pressure. The residue was purified by flashchromatography over silica gel (gradient of 5-15% ethyl acetate inhexanes) to afford the title compound (431 mg) as a colorless liquid. ¹HNMR (400 MHz, CDCl₃): 1.55-1.66 (1H, m), 1.96-2.06 (1H, m), 2.31-2.41(5H, m), 2.43-2.48 (2H, m) 3.48 (1H, s), 3.85 (3H, s), 6.75 (1H, s),7.23 (1H, s).

Step 2: 1-Chloro-5-cyclobutyl-4-methoxy-2-methyl-benzene

To a mixture of 1-(5-chloro-2-methoxy-4-methyl-phenyl)-cyclobutanol (428mg) and triethyl silane (0.362 mL) in anhydrous DCM (20 mL) at −78° C.under argon atmosphere was added dropwise boron trifluoride etherate(0.237 mL) and the reaction mixture was allowed to warm to −40° C.within a period of 3 h. Stirring was then continued at −40° C. foranother 2 h. The reaction mixture was then poured into 10% aqueous KHCO₃solution (30 mL) and was extracted with DCM (3×30 mL). The combinedorganic layers were dried (Na₂SO₄), filtered, and evaporated. Theresidue was purified by column chromatography over silica gel (gradientof 0-5% ethyl acetate in hexanes) to provide the title compound (370 mg)as a colorless liquid. ¹H NMR (400 MHz, CDCl₃): 1.78-1.81 (1H, m),1.91-2.06 (3H, m), 2.24-2.32 (5H, m), 3.62-3.75 (I H, m), 3.38 (3H, s),6.63 (1H, s), 7.12 (1H, s).

Step 3: 4-Chloro-2-cyclobutyl-5-methyl-phenol

The title compound was obtained in analogy to Intermediate A19, Step 3,from 4-chloro-2-cyclobutyl-5-methyl-phenol by treatment with BBr₃ in DCMas a brown solid (327 mg). ¹H NMR (400 MHz, CDCl₃): 1.82-1.89 (1H, m),1.98-2.16 (3H, m), 2.27 (3H, s), 2.31-2.42 (2H, m) 3.53-3.59 (1H, m),4.50 (1H, s), 6.61 (1H, s), 7.09 (1H, s).

Intermediate A34

4-(tert-Butyl)-2-chloro-5-hydroxy benzonitrile

Step 1: 5-Bromo-2-(tert-butyl)-4-chlorophenol

To a solution of 3-bromo-4-chlorophenol (2.0 g, CAS: 13659-24-0) inacetic acid (6.0 mL) were added tert-butanol (1.07 g, 1.36 mL) followedby sulfuric acid (946 mg, 517 μL) at room temperature under an argonatmosphere. The mixture was heated to 70° C. for 80 hours. Moretert-butanol (715 mg, 905 μL) and sulfuric acid (756 mg, 413 μL) wereadded and the mixture was heated to 90° C. for another 24 hours. Thereaction mixture was cooled to room temperature and was then poured intoice/water. The aqueous layer was extracted twice with ethyl acetate. Theorganic layers were washed once with brine, dried over Na₂SO₄, filteredand evaporated. Residual tert-butanol was removed by evaporation fromtoluene (200 mL) to dryness. The crude material was purified by flashchromatography (0% to 20% ethyl acetate in heptane) to give the titlecompound as a light brown liquid (506 mg, 19%). MS (ESI): m/z=263.11[M−H]⁻.

Step 2; 4-(tert-Butyl)-2-chloro-5-hydroxybenzonitrile

5-Bromo-2-(tert-butyl)-4-chlorophenol (501 mg),1,1′-bis(diphenylphosphino)-ferrocene (31.6 mg), zinc granules (4.97mg), zinc cyanide (123 mg), zinc acetate (14 mg),tris(dibenzylidene-acetone)dipalladium(0) (17.4 mg) were dissolved indimethylformamide (5.0 mL) and water (50 μL) at room temperature. Themixture was then subjected to microwave irradiation for 30 minutes at180° C. The reaction mixture was cooled to room temperature and was thenpoured then into ice/water. The aqueous layer was acidified with sat.NH₄Cl solution and was extracted twice with ethyl acetate. The organiclayers were washed once with brine, dried over Na₂SO₄, filtered andevaporated. Residual DMF was removed by evaporation from toluene (150mL) to dryness. The crude material was purified by flash chromatography(0% to 20% ethyl acetate in heptane) to give the title compound as alight yellow solid (71 mg, 18%). MS (ESI): m/z=208.1 [M−H]⁻.

Intermediate A35

5-tert-butyl-2-chloro-4-hydroxy-benzonitrile

Step 1: 4-bromo-2-tert-butyl-5-chloro-phenol

To a sealable vessel containing 4-bromo-3-chlorophenol (23 g, 111 mmol)was added acetic acid (115 mL), tBuOH (48 mL, 499 mmol), and sulfuricacid (30 mL, 333 mmol). The vessel was sealed and heated to 90° C. withvigorous stirring. After 18 h, an additional charge of tBuOH (48 mL, 499mmol), and sulfuric acid (30 mL, 333 mmol) was added, and heating wascontinued at 90° C. After 5 h, the reaction was cooled to roomtemperature then partitioned between ethylacetate and water. The layerswere separated, and the aqueous phase washed again with ethylacetate.The combined organic phases were washed twice with water, once withbrine, dried over MgSO₄, filtered and concentrated. The resulting crudemixture was purified on SiO₂, eluting first with 100% hexanes, thenramping to 25% ethylacetate in hexanes to yield 9.76 g of the titlecompound which was used in the next step without further purification(60% pure, measured by NMR).

Step 2: 5-tert-butyl-2-chloro-4-hydroxy-benzonitrile

To 4-bromo-2-tert-butyl-5-chloro-phenol (9.76 g, 60% pure, 22.2 mmol)was added DMF (80 mL) then CuCN (4 g, 44.7 mmol). The resulting mixturewas heated to 170° C. for 8 h Upon reaction completion, the mixture wascooled then partitioned between ethylacetate and water. The resultingsuspension was filtered over celite and rinsed with ethylacetate. Thelayers were separated, and the aqueous phase washed again withethylacetate. The combined organic phases were washed with water, brine,dried over MgSO₄, filtered and concentrated. The resulting crude mixturewas purified on SiO2, eluting with 0-60% ethylacetate in hexanes toyield 2.59 g of the title compound (56% yield).

Intermediate A36

5-tert-butyl-2-fluoro-4-hydroxy-benzonitrile

Step 1: 2-tert-butyl-4-chloro-5-fluoro-phenol

The title compound was prepared in analogy to intermediate A35, step 1,from 4-chloro-3-fluorophenol (5 g) and was obtained (4.4 g, 64%).

Step 2: 5-tert-butyl-2-fluoro-4-hydroxy-benzonitrile

To 2-tert-butyl-4-chloro-5-fluoro-phenol (108 mg, 0.53 mmol) was addeddioxane/water (1:1, 2 mL), potassium acetate (10 mg, 0.11 mmol), andK₄[Fe(CN)₆].3H₂O (113 mg, 0.27 mmol). Nitrogen gas was bubbled throughfor 20 minutes. 2-Di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl(11 mg, 0.027 mmol) and[(2-Di-tert-butylphosphino-2,4,6-triisopropyl-1,1-biphenyl)-2-(2-amino-1,1-biphenyl)]palladium(II) methanesulfonate (21 mg, 0.027 mmol) were added and themixture was heated to 100° C. for 3 h. Upon reaction completion, themixture was cooled then partitioned between ethylacetate and brine. Theresulting suspension was filtered over celite and rinsed withethylacetate. The layers were separated, the organic phases were washedtwice with brine, dried over magnesiumsulfate, filtered andconcentrated. The resulting crude mixture was purified on SiO2 elutingwith 0-100% ethylacetate in hexanes) to yield 61.3 mg of the titlecompound (60% yield).

Intermediates B

Intermediate B1:

4-Chloro-5-methyl-2-phenylphenol

Step 1: 5-Chloro-2-methoxy-4-methylaniline

To a solution of 1-chloro-4-methoxy-2-methyl-5-nitrobenzene (0.15 g,prepared as described in WO2011/141716) in THF (0.22 mL) were addedFe(acac)₃ (52.6 mg, CAS: 14024-18-1) and 1,1,3,3-tetramethyldisiloxane(300 mg, CAS: 3277-26-7) and the reaction mixture was stirred at refluxin a sealed tube for 15 hours. The reaction mixture was allowed to coolto rt, treated with EtOAc (5 mL) and extracted with aqueous 25% HClsolution (2 mL). The aqueous layer was extracted once more with EtOAc (5mL). The aqueous layer was then adjusted to approx. pH 8 to 9 usingsolid NaHCO₃ and was then extracted three times with EtOAc. The combinedorganic layers were dried over MgSO₄, filtered and evaporated to givethe title compound as a brown solid (0.1 g: 78%). MS (ESI): m/z=172.4[M+H]⁺.

Step 2: 1-Chloro-5-iodo-4-methoxy-2-methylbenzene

To conc. aqueous HCl (127 μL) at 0° C. was added NaNO₂ (57.5 mg, CAS:7632-00-0).

To this mixture was added dropwise over 7 minutes a solution of5-chloro-2-methoxy-4-methylaniline (0.13 g) in AcOH (1.5 mL) and theresulting mixture was stirred at rt for 30 minutes. This mixture wasadded dropwise via syringe to a stirred solution of KI (377 mg, CAS:7681-11-0) in 48% aqueous HBr (2 mL) at room temperature. The brownmixture was stirred at rt for another 2 hours. The reaction mixture waspoured on 2M aqueous Na₂CO₃ solution and EtOAc and the layers wereseparated. The aqueous layer was extracted twice with EtOAc. The organiclayers were washed once with brine, dried over MgSO₄, filtered andevaporated. The residue was purified by silica gel chromatography on a10 g column using an MPLC (ISCO) system eluting with a gradient ofn-heptane in EtOAc (100/0 to 50/50) to give the title compound as alight brown solid (0.134 g; 63%). MS (EI): m/z=282[M].

Step 3: 4-Chloro-2-iodo-5-methylphenol

To a solution of I-chloro-5-iodo-4-methoxy-2-methylbenzene (1.13 g) inDCM (20 mL) was added dropwise at 0° C. tribromoborane 1M in DCM (4.2mL, CAS: 10294-334) over 15 minutes. The reaction mixture was stirredfor 4 hours at rt. The reaction mixture was poured on H₂O (60 mL) andDCM (60 mL) and the layers were separated. The aqueous layer wasextracted a second time with DCM (60 mL). The organic layers were washedwith brine (60 mL), dried over MgSO₄, filtered and concentrated in vacuoto give the title compound as a light yellow solid (1.023 g, 95%). MS(ESI): m/z=266.907 [M−H]⁻.

Step 4: 4-Chloro-5-methyl-2-phenylphenol

To a solution of 4-chloro-2-iodo-5-methylphenol (100 mg) in DME (2 mL)was added phenylboronic acid (45.4 mg, CAS: 98-80-6) and 2M aqueousNa₂CO₃ (1 mL). The reaction mixture was stirred for 15 minutes underargon atmosphere. Pd(II)acetate (4.18 mg, CAS: 3375-31-3) andtriphenyphosphine (9.77 mg, CAS: 603-35-0) were added. The reactionmixture was stirred for 2 hours at 90° C. The reaction mixture waspoured on 10% aqueous NaHCO₃ solution (30 mL) and EtOAc (30 mL) and thelayers were separated. The aqueous layer was extracted a second timewith EtOAc (30 mL). The organic layers were washed with brine (30 mL),dried over MgSO₄, filtered and concentrated under vacuum. The compoundwas purified by silica gel chromatography on a 20 g column using an MPLC(Flashmaster) system eluting with a gradient of n-heptane in EtOAc(100/0 to 70/40) to give the title compound as alight yellow oil (0.077g, 95%). MS (EI): m/z=218 [M]⁺.

The following intermediates were made in analogy to intermediate B1,step 4, from 4-chloro-2-iodo-5-methylphenol (intermediate B1, step 3)and the corresponding aryl boronic acid or aryl borolane building blockas indicated in the following table:

Inter- Building block/ mediate Systematic Name intermediate MS, m/z  B2

2-chlorophenylboronic acid CAS: 3900-89-8 MS (EI): 252.0 [M]⁺  B3

3-chlorophenylboronic acid CAS: 63503-60-6 MS (ESI): 251.003 [M − H]⁻ B4

4-chlorophenylboronic acid CAS: 1679-18-1 MS (ESI): 251.003 [M − H]⁻  B5

3-cyanophenylboronic acid CAS: 150255-96-2 MS (ESI): 242.048 [M − H]⁻ B6

3-(methylsulfonyl)phenyl- boronic acid CAS: 373384-18-0 MS (ESI):295.020 [M − H]⁻  B7

2-(methylsulfonyl)phenyl- boronic acid CAS: 330804-03-0 MS (EI): 296.0[M]⁺  B8

3-(piperidine-1- carbonyl)phenylboronic acid CAS: 850568-34-2 MS (ESI):330.127 [M + H]⁺  B9

3-(cyclohexylcarbamoyl) phenylboronic acid CAS: 850567-25-8 MS (ESI):344.143 [M + H]⁺ B10

3-(morpholine-4- carbonyl)phenylboronic acid CAS: 723281-55-8 MS (ESI):332.104 [M + H]⁺ B11

3-carbamoylphenylboronic acid CAS: 351422-73-6 MS (ESI): 260.047 [M −H]⁻ B12

3-(dimethylcarbamoyl)- phenylboronic acid CAS: 373384-14-6 MS (ESI):290.095 [M + H]⁺ B13

3-(phenylcarbamoyl)- phenylboronic acid CAS: 397843-71-9 MS (ESI):338.09 [M + H]⁺ B14

3-carbamoyl-5- chlorophenylboronic acid CAS: 957120-53-5 MS (ESI):294.01 [M − H]⁻ B15

5-(cyclopropylcarbamoyl)- 2-fluorophenylboronic acid CAS: 874289-54-0 MS(ESI): 320.08 [M + H]⁺ B17

N-(2-methoxyethyl)-3- (4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide ( CAS: 1073353-64-6 MS (ESI): 320.11 [M + H]⁺ B18

2-chloropyridin-3- ylboronic acid CAS: 381248-04-0 MS (ESI): 254.01 [M +H]⁺ B19

6-chloropyridine-2-boronic acid pinacol ester CAS: 652148-92-0 MS (ESI):224.998 [M + H]⁺ B20

5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2- yl)nicotinamide CAS:1169402-51-0 MS (ESI): 263.06 [M + H]⁺ B21

6-methoxypyridin-2- ylboronic acid CAS: 372963-51-4 MS (ESI): 250.06[M + H]⁺ B36

N-(2-hydroxyethyl)-3- (4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide CAS: 943911-66-8 MS (ESI): 306.1 [M + H]⁺ B38

5-(dimethylcarbamoyl)-2- fluorophenylboronic acid CAS: 874289-46-0 MS(ESI): 308.1 [M + H]⁺ B40

2-fluoro-5-(morpholine-4- carbonyl)phenylboronic acid CAS: 1072951-41-7MS (ESI): 350.1 [M + H]⁺ B42

3-(methoxycarbonyl)- phenylboronic acid CAS: 99769-19-4 MS (ESI): 275.2[M − H]⁻ B44

3-(3-methoxy-3- oxopropylcarbamoyl)- phenylboronic acid CAS: 957034-72-9MS (ESI): 348.2 [M + H]⁺ B46

3-(2-ethoxy-2- oxoethylcarbamoyl)phenyl boronic acid CAS: 1072945-97-1MS (ESI): 348.1 [M + H]⁺ B49

5-(methoxycarbonyl)-2- methylphenylboronic acid CAS: 876189-18-3 MS(ESI): 289.2 [M − H]⁻ B52

5-carbamoyl-2- (trifluoromethoxy)phenyl- boronic acid eMolecules#BB-4033 MS (ESI): 346.1 [M + H]⁺ B53

2-methoxypyridin-3- ylboronic acid CAS: 163105-90-6 MS (ESI): 250.1 [M +H]⁺Intermediate B16:

6-Hydroxy-biphenyl-3-carbonitrile

Step 1: 4-Hydroxy-3-iodo-benzonitrile

To a solution of 4-hydroxy-benzonitrile (5 g, CAS: 767-00-0) in NH₄OH(225 mL) was added a solution of KI (34.14 g, CAS: 7681-11-0) and 12(10.65 g, CAS: 7553-56-2) in H₂O (50 mL). The reaction mixture wasstirred at rt for 16 hours. The reaction mixture was filtered and thefiltrate was evaporated. The residue was dissolved in DCM (250 mL) andwas washed with H₂O (2×150 mL), saturated aqueous NaS₂O₃ solution (100mL) and brine (100 mL). The organic layer was dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure to give thetitle compound (8.44 g, 82%) that was used in the next step withoutfurther purification. LC-MS: (ESI): m/z=244.0 [M−H]⁻.

Step 2: 6-Hydroxy-biphenyl-3-carbonitrile

The title compound was obtained in analogy to intermediate B1, step 4,from 4-hydroxy-3-iodo-benzonitrile and phenylboronic acid (CAS: 98-80-6)as a colorless solid (0.580 g, 73%). ¹H NMR (400 MHz, CDCl₃): 5.72 (1H,s), 7.03-7.07 (1H, d, J=4), 7.40-7.42 (2H, d, J=8), 7.44-7.56 (5H, m).

Intermediate B26:

4-Chloro-5-methyl-2-oxazol-5-yl-phenol

Step 1: 5-Chloro-2-methoxy-4-methyl-benzaldehyde

To a solution of 1-chloro-5-iodo-4-methoxy-2-methylbenzene (1.0 g,intermediate B1, step 2) in anhydrous THF (25 mL) was added n-BuLi (1.7mL, 2.5M solution in hexane) dropwise at −78° C. under nitrogenatmosphere and the reaction mixture was stirred at −78° C. for 2 hours.Then, DMF (0.329 mL) dissolved in anhydrous THF (2 mL) was addeddropwise to the reaction mixture at −78° C. and the solution was stirredat −78° C. for 2 hours. The reaction mixture was quenched with saturatedaqueous NH₄Cl solution and was extracted with EtOAc (2×50 mL). Thecombined organic layers were washed with brine (50 mL), dried overNa₂SO₄, filtered and evaporated under reduced pressure to give the titlecompound as yellow solid (0.685 g, 76%). Rf=0.6 (10% EtOAc/hexane).

Step 2: 5-(5-Chloro-2-methoxy-4-methyl-phenyl)-oxazole

To a stirred solution of 5-chloro-2-methoxy-4-methyl-benzaldehyde (500mg) in MeOH (20 mL) was added tosylmethyl isocyanide (582 mg, CAS:36635-61-7), followed by K₂CO₃ (561 mg) and the resulting mixture wasrefluxed for 3 hours. Then, MeOH was evaporated and the residue waspurified by flash chromatography over silica gel (5-10% EtOAc/hexane) togive the title compound as an off white solid (294 mg, 49%). MS (ESI):m/z=224.0 [M+H]⁺.

Step 3: 4-Chloro-5-methyl-2-oxazol-5-yl-phenol

The title compound was obtained in analogy to intermediate B1, step 3,from 5-(5-chloro-2-methoxy-4-methyl-phenyl)-oxazole (292 mg) as a brownsolid (0.266 g, 97%). MS (ESI): m/z=210.2 [M+H]⁺.

Intermediate B30:

4-Chloro-5-methyl-2-(2-methyl-2H-pyrazol-3-yl)-phenol

Step 1: 5-(5-Chloro-2-methoxy-4-methyl-phenyl)-1-methyl-1H-pyrazole

To a mixture of 1-chloro-5-iodo-4-methoxy-2-methyl-benzene (500 mg,intermediate B1, step 2),1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole(442 mg, CAS: 847818-74-0) and K₂CO₃ (733 mg) in dioxane (12 ml) andwater (4 ml) was added PdCl₂(PPh₃)₂—CH₂Cl₂ (25 mg) and the reactionmixture was heated to 110° C. for 16 h. The reaction mixture was dilutedwith ethyl acetate (50 ml), filtered through celite and the filtrate wasevaporated. The resulting residue was purified by column chromatographyover silica gel (0-20% EtOAc/hexane) to obtain5-(5-chloro-2-methoxy-4-methyl-phenyl)-1-methyl-1H-pyrazole (365 mg,87%) as brown sticky solid. MS (ESI): m/z=236.7 [M+H]⁺.

Step 2: 4-Chloro-5-methyl-2-(2-methyl-2H-pyrazol-3-yl)-phenol

To a solution of5-(5-chloro-2-methoxy-4-methyl-phenyl)-1-methyl-1H-pyrazole (355 mg) inDCM (20 ml) at 0° C. was added BBr₃ (1M solution in DCM, 3 mL) and thereaction mixture was stirred at 25° C. for 3 h. All volatiles were thenremoved in vacuo and the remaining residue was dissolved in DCM (50 ml)and washed with 10% aqueous NaHCO₃ solution and brine. The organic layerwas dried over Na₂SO₄ and concentrated. The resulting crude material waspurified by column chromatography over silica gel (0-30% EtOAc/hexane)to afford 4-chloro-5-methyl-2-(2-methyl-2H-pyrazol-3-yl)-phenol (138 mg,41%) as yellow solid. MS (ESI): m/z=223 [M+H]⁺.

Intermediate B31:

4-Chloro-6-hydroxy-biphenyl-3-carbonitrile

Method A:

Step 1: 5-Bromo-2-chloro-4-hydroxy-benzonitrile

To a solution of 2-chloro-4-hydroxy-benzonitrile (4.0 g, CAS: 3336-16-1)in anhydrous acetonitrile (80 ml) was added TfOH (2.53 ml) drop wise at−30° C. and the reaction mixture was stirred at −30° C. for 10 min. ThenNBS (6.49 g) was added and the mixture was stirred at −30° C. for 5 min.The reaction mixture was then allowed to warm to 25° C. and was stirredat 25° C. for 16 h. The reaction mixture was quenched with saturatedaqueous sodium bisulfite solution and extracted with EtOAc. The combinedorganic layers were washed with brine, dried over Na₂SO₄ and filtered.The filtrate was evaporated under reduced pressure and the resultingresidue was purified by column chromatography over silica gel (2-6%EtOAc/hexane) to afford 5-bromo-2-chloro-4-hydroxy-benzonitrile (1.2 g,20%) as an off white solid. MS (ESI): m/z=231.6 [M+H]⁺.

Step 2: 5-Bromo-2-chloro-4-methoxymethoxy-benzonitrile

To a suspension of NaH (62 mg, 60% in mineral oil) in anhydrous THF (10mL) at 0° C. was added a solution of5-bromo-2-chloro-4-hydroxy-benzonitrile (300 mg) in anhydrous THF (5 mL)and the reaction mixture was stirred at 25° C. for 30 min. Then MOM-Cl(0.147 ml) was added dropwise and the reaction mixture was stirred at25° C. for 3 h. The reaction mixture was quenched with water and wasextracted with EtOAc. The combined organic layers were washed withbrine, dried over Na₂SO₄ and evaporated under reduced pressure. Theresulting crude material was purified by column chromatography oversilica gel (0-3% EtOAc/hexane) to afford5-bromo-2-chloro-4-methoxymethoxy-benzonitrile (315 mg, 88%) as an offwhite solid. ¹H-NMR (δ, CDCl₃): 3.51 (s, 3H), 5.30 (s, 2H), 7.28 (s,1H), 7.81 (s, 1H).

Step 3: 4-Chloro-6-hydroxy-biphenyl-3-carbonitrile

To a mixture of 5-bromo-2-chloro-4-methoxymethoxy-benzonitrile (100 mg)and phenyl boronic acid (132.3 mg, CAS: 98-80-6) in anhydrous DMF (50mL) in a sealed tube was added K₂CO₃ (149.7 mg) at 25° C. and thereaction mixture was purged with argon for 10 min. ThenPd(dppf)Cl₂—CH₂Cl₂ complex (8.85 mg) was added and the mixture was againpurged with argon for 10 min and then heated to 120° C. for 16 h. Thereaction mixture was cooled to 25° C. and filtered. The filtrate wasevaporated under reduced pressure and the resulting residue was purifiedby column chromatography over silica gel (5-7% EtOAc/hexane) to afford4-chloro-6-hydroxy-biphenyl-3-carbonitrile (43 mg, 44%) as off whitesolid. ¹H-NMR (δ, CDCl₃): 5.91 (s, 1H), 7.13 (s, 1H), 7.39 (dd, 2H),7.44-7.56 (m, 4H).

Method B:

Step 1: 5-iodo-2-chloro-4-hydroxy-benzonitrile

To a solution of 2-chloro-4-hydroxybenzonitrile (1.18 g, CAS: 3336-16-1)in acetic acid (10 mL) and DCM (10 mL) was added concentrated sulfuricacid (100 μL) and then N-iodosuccinimide (1.66 g) in one portion at rtunder an argon atmosphere. The mixture was stirred at rt for 16 hours.The reaction mixture was then poured into ice/water and was extractedtwo times with ethyl acetate. The organic layers were washed once withbrine, dried over Na₂SO₄, filtered and evaporated. The crude materialwas adsorbed onto silica gel and was then purified by flashchromatography (ISCO, 100 g silica gel cartridge, gradient of 0% to 20%EtOAc in heptane). The fractions containing the desired product alongwith some di-iodinated side products were combined, evaporated and driedat high vacuum. The residue (1.42 g) was further purified by preparativeHPLC (Column: Gemini NX 3u 50×4.6 mm; Eluent: 2% formic acid, 98% CH₃CN)to provide the title compound (770 mg) as an off white solid. MS (ESI⁻):m/z=278.0 [M−H]⁻.

Step 2: 4-Chloro-6-hydroxy-biphenyl-3-carbonitrile

2-Chloro-4-hydroxy-5-iodobenzonitrile (350 mg), phenylboronic acid (160mg) and sodium carbonate (398 mg) were combined with DMF (13.0 mL) andwater (2.0 mL) at rt under an argon atmosphere. Ten,[1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II), complexwith DCM (133 mg) was added to the orange suspension. The reactionmixture was three times evaporated and purged with argon and then heatedto 80° C. for 3.5 hours. The mixture was cooled to room temperature,poured into ice/water and was then acidified with saturated NH₄Clsolution. The aqueous layer was extracted twice with ethyl acetate. Theorganic layers were washed with brine, dried over Na₂SO₄, filtered andevaporated. The crude material was purified by flash chromatography(ISCO, silica gel, 40 g cartridge, 100% CH₂Cl₂ and thenCH₂Cl₂/CH₃CN=96/4). The appropriate fractions were combined andevaporated to provide the title compound (150 mg) as an off white solid.

MS (ESI⁻): m/z=228.1 [M−H]⁻. NMR complies with the material describedabove from method A.

The following Intermediates were prepared in analogy to intermediateB31, either via method A from 5-bromo-2-chloro-4-hydroxy-benzonitrile(intermediate B31, step 1), or via method B from5-iodo-2-chloro-4-hydroxy-benzonitrile, and the boronic acid precursorsas indicated in the table below:

Inter- Building block/ mediate Systematic Name intermediate MS, m/z B324-Chloro-4′-fluoro-6- hydroxy-biphenyl-3- carbonitrile

4-fluoro phenyl boronic acid CAS: 1765-93-1 Method A MS (ESI): 245.6[M + H]⁺ B33 4′-Chloro-5′-cyano-2′- hydroxy-biphenyl-3- carboxylic acidmethylamide

3-(N- methylarninocarbonyl) phenylboronic acid CAS: 832695-88-2 Method AMS (ESI): 287.1 [M + H]⁺ B84 2-chloro-5-(2- fluorophenyl)-4-hydroxybenzonitrile

2-fluoro phenyl boronic acid CAS: 1993-03-9 Method B MS(ESI): 248.1 [M +H]⁺ B85 2-ch1oro-5-(3- f1uorophenyl)- 4-hydroxybenzonitrile

3-fluoro phenyl boronic acid CAS: 768-35-4 Method B MS(ESI): 246.1 [M −H]⁻ B89 2-chloro-5-(2-fluoro-5- propan-2-yloxypbenyl)-4-hydroxybenzonitrile

(2-fluoro-5-propan-2- yloxyphenyl) boronic acid CAS: 849062-30-2 MethodB MS(ESI): 304.2 [M − H]⁻Intermediate 835:

4-Chloro-6-hydroxy-3′-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-3-carbonitrile

Step 1: 3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile

To a solution of 3-cyanophenyl boronic acid (2.5 g, CAS: 150255-96-2) inanhydrous THF (150 ml) under an atmosphere of nitrogen were addedpinacol (2.95 g) and Na₂SO₄ (10 g) at 25° C. The reaction mixture wasstirred for 12 h at 25° C. under an atmosphere of nitrogen. Then, Na₂SO₄was filtered off and all volatiles were evaporated. The residue waspartitioned between ethyl acetate and water. The organic layer was thenseparated, dried over Na₂SO₄ and concentrated to afford the titlecompound (4.72 g) as off white solid which was directly used in the nextreaction step without further characterization.

Step 2:N-Hydroxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamidine

To a solution of-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile (4.65 g) inethanol (150 ml) were added DIPEA (7.15 mL) and hydroxyl aminehydrochloride (3.53 g) at 25° C. The reaction mixture was then refluxedfor 3 h. All volatiles were evaporated in vacuo and the residue waspartitioned between ethyl acetate and water. The organic layer wasseparated, dried over Na₂SO₄ and concentrated to affordN-hydroxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamidinealong with some impurities (5.7 g) as an off white, sticky solid. MS(ESI): m/z=262.8 [M+H]⁺.

Step 3:5-Methyl-3-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-[1,2,4]oxadiazole

A solution ofN-hydroxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamidine(5.7 g) in acetic anhydride (100 mL) was refluxed for 3 h. Aceticanhydride was evaporated and the residue was partitioned between waterand ethyl acetate. The ethyl acetate layer was separated, washed withaqueous NaHCO₃ solution, water and brine and dried over Na₂SO₄ andconcentrated. The crude product was purified by column chromatographyover silica gel (0-5% EtOAc/hexane) to afford the title compound (3.5 g)as an off white solid. MS (EST): m/z=287.0 [M+H]⁺.

Step 4:4-Chloro-6-hydroxy-3′-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-3-carbonitrile

The title compound was prepared in analogy to Intermediate B31, step 3,from 5-bromo-2-chloro-4-methoxymethoxy-benzonitrile (Intermediate B32,step 2) (300 mg) and5-methyl-3-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-[1,2,4]oxadiazole(932 mg) and was obtained as off white solid (190 mg, 56%). MS (ESI):m/z=310.2 [M−H]⁻.

Intermediate B37:

4-Chloro-6-hydroxy-3′-(5-methyl-[1,3,4]oxadiazol-2-yl)-biphenyl-3-carbonitrile

Step 1: 4′-Chloro-5′-cyano-2′-hydroxy-biphenyl-3-carboxylic acid methylester

The title compound was prepared in analogy to Intermediate B31, step 3,from 5-bromo-2-chloro-4-methoxymethoxy-benzonitrile (Intermediate B31,step 2) (1.0 g) and 3-methoxycabonyl phenyl boronic acid (973 mg, CAS:99769-19-4) and was obtained as off white solid (430 mg, 41%). MS (ESI):m/z=286 [M−H]⁻.

Step 2: 4′-Chloro-5′-cyano-2′-methoxy-biphenyl-3-carboxylic acid methylester

To a solution of 4′-chloro-5′-cyano-2′-hydroxy-biphenyl-3-carboxylicacid methyl ester (650 mg) in anhydrous DMF (30 mL) were added Cs₂CO₃(1.10 g) and methyliodide (0.169 mL) at 25° C. The reaction mixture wasstirred at 25° C. for 16 h and then filtered. The filtrate wasevaporated under reduced pressure and the remaining residue was purifiedby column chromatography over silica gel (10-15% EtOAc/hexane) to affordthe title compound (490 mg, 71%) as an off white solid that was usedwithout further characterization.

Step 3: 4′-Chloro-5′-cyano-2′-methoxy-biphenyl-3-carboxylic acid

To a solution of 4′-chloro-5′-cyano-2′-methoxy-biphenyl-3-carboxylicacid methyl ester (490 mg) in mixture of THF and water (45 mL) was addedLiOH—H₂O (136.6 mg) at 25° C. and the reaction mixture was stirred at rtfor 12 h. The reaction mixture was then diluted with EtOAc (20 mL) andthe layers were separated. The aqueous layer was acidified by additionof 6N HCl and was extracted with EtOAc. The combined extracts werewashed with brine, dried over Na₂SO₄ and concentrated to obtain thetitle compound (410 mg, 88%) as an off white solid. MS (ESI): m/z=286.1[M−H]⁻.

Step 4: 4′-Chloro-5′-cyano-2′-methoxy-biphenyl-3-carboxylic acidN′-acetyl-hydrazide

To a solution of 4′-chloro-5′-cyano-2′-methoxy-biphenyl-3-carboxylicacid (410 mg) in anhydrous DMF (30 mL) were added HBTU (812.1 mg) andDIPEA (0.76 mL) at 25° C. The reaction mixture was stirred for 10 minand then acetic acid hydrazide (211.42 mg) was added and stirring wascontinued for 16 h. The solvent was evaporated and to the remainingresidue were added EtOAc and water. The organic layer was separated,dried over Na₂SO₄ and concentrated. The residue was purified by columnchromatography over silica gel (2-3% MeOH/DCM) to afford the titlecompound (470 mg, 96%) as an off white solid. MS (ESI): m/z=344.2[M+H]⁺.

Step 5:4-Chloro-6-methoxy-3′-(5-methyl-[1,3,4]oxadiazol-2-yl)-biphenyl-3-carbonitrile

A solution of 4′-chloro-5′-cyano-2′-methoxy-biphenyl-3-carboxylic acidN′-acetyl-hydrazide (400 mg) in POCl₃ (10 mL) was heated to 110° C. for6 h. The reaction mixture was then cooled to 25° C. and all volatileswere removed under reduced pressure. To the remaining residue was addedsat. NaHCO₃ solution (15 mL) and the mixture was extracted with EtOAc.The combined extracts were dried over Na₂SO₄ and concentrated. Theresidue was purified by column chromatography over silica gel (10-15%EtOAc/hexane) to afford the title compound (130 mg, 34%) as an off whitesolid. MS (ESI): m/z=326.2 [M+H]⁺.

Step 6:4-Chloro-6-hydroxy-3′-(5-methyl-[1,3,4]oxadiazol-2-yl)-biphenyl-3-carbonitrile

To a solution of4-chloro-6-methoxy-3′-(5-methyl-[1,3,4]oxadiazol-2-yl)-biphenyl-3-carbonitrile(110 mg) in anhydrous DCM (10 mL) was added BBr₃ (0.4 mL) at 0° C. Thereaction mixture was stirred at 25° C. for 28 h. Again BBr₃ (0.5 mL) wasadded and reaction mixture was stirred for another 16 h. All volatileswere removed under reduced pressure and the residue was purified bycolumn chromatography over silica gel (30-45% EtOAc/hexane) to affordthe title compound (80 mg, 76%) as an off white solid. MS (EST):m/z=310.2 [M−H]⁻.

Intermediate B39:

3-(4-Chloro-5-cyano-2-hydroxy-phenyl)-N,N-dimethyl-benzamide

Step 1:3-[4-Chloro-5-cyano-2-(methoxymethoxy)phenyl]-N,N-dimethyl-benzamide

The title compound was prepared in analogy to Intermediate B31, step 3,from 5-bromo-2-chloro-4-methoxymethoxy-benzonitrile (Intermediate B31,step 2) (48.9 mg) and 3-(dimethylcarbamoyl)phenylboronic acid (40.9 mg,CAS: 373384-14-6) and was obtained as light yellow gum (43 mg, 71%). MS(ESI): m/z=698.3 [2M+H]⁺.

Step 2: 3-(4-Chloro-5-cyano-2-hydroxy-phenyl)-N,N-dimethyl-benzamide

To solution of3-[4-chloro-5-cyano-2-(methoxymethoxy)phenyl]-N,N-dimethyl-benzamide(40.0 mg) in dioxane (1 mL) was added dropwise 4N HCl in dioxane (150μl) at 0° C. The reaction mixture was then stirred at rt for 4 h.Additional 4N HCl in dioxane (100 μl) was added and the resultingsuspension was stirred at rt overnight. The reaction mixture wasconcentrated to dryness and then co-evaporated from DCM three times. Theresulting off white solid (34 mg, 97%) was used in the next reactionstep without further purification. MS (ESI): m/z=301.1 [M+H]⁺.

Intermediate B41:

2-Chloro-4-hydroxy-5-[3-(morpholine-4-carbonyl)phenyl]benzonitrile

Step 1:2-Chloro-4-(methoxymethoxy)-5-[3-(morpholine-4-carbonyl)phenyl]benzonitrile

The title compound was prepared in analogy to Intermediate B31, step 3,from 5-bromo-2-chloro-4-methoxymethoxy-benzonitrile (Intermediate B31,step 2) (50.0 mg) and 3-(morpholine-4-carbonyl)phenylboronic acid (51.0mg, CAS: 723281-55-8) and was obtained as white solid (53 mg, 76%). MS(ESI): m/z=387.2 [M+H]⁺.

Step 2:2-Chloro-4-hydroxy-5-[3-(morpholine-4-carbonyl)phenyl]benzonitrile

The title compound was prepared in analogy to Intermediate B39, step 2,from2-chloro-4-(methoxymethoxy)-5-[3-(morpholine-4-carbonyl)phenyl]benzonitrile(49.9 mg) and was obtained as off white solid (44 mg, 99%). MS (ESI):m/z=343.11 [M+H]⁺.

Intermediate B54:

2-Chloro-4-hydroxy-5-(2-methoxy-3-pyridyl)benzonitrile

Step 1: 2-Chloro-4-(methoxymethoxy-5-(2-methoxy-3-pyridyl)benzonitrile

The title compound was prepared in analogy to Intermediate B31, step 3,from 5-bromo-2-chloro-4-methoxymethoxy-benzonitrile (intermediate B31,step 2) (50.0 mg) and 2-methoxypyridin-3-ylboronic acid (33.2 mg,eMolecules #BB-4033) and was obtained as a white solid (43 mg, 78%). MS(ESI): m/z=305.1 [M+H]⁺.

Step 2: 2-Chloro-4-hydroxy-5-(2-methoxy-3-pyridyl)benzonitrile

The title compound was prepared in analogy to Intermediate B39, step 2,from 2-chloro-4-(methoxymethoxy)-5-(2-methoxy-3-pyridyl)benzonitrile(41.1 mg) and was obtained as an off white solid (35.2 mg, 100%). MS(ESI): m/z=261.1 [M+H]⁺.

Intermediate B58

4-Chloro-2-[2-fluoro-5-(2-methylpropoxy)phenyl]-5-methylphenol

4-Chloro-2-iodo-5-methylphenol (intermediate B1, step 3, (80 mg),(2-fluoro-5-isobutoxyphenyl)boronic acid (75.8 mg, CAS: 1217500-65-6)and sodium carbonate (94.7 mg) were combined with DMF (5.0 mL) and water(0.85 mL) at rt under an argon atmosphere. Then,[1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) complexwith dichloromethane (31.6 mg, CAS: 95464-05-4) was added to the orangesuspension. The reaction mixture was heated to 80° C. for 3 hours andwas then cooled and kept at rt for 64 hours. The reaction mixture waspoured into ice/water and was acidified with saturated NH₄Cl solution.The aqueous layer was extracted twice with ethyl acetate. The organiclayers were washed once with brine, dried over Na₂SO₄, filtered andevaporated to dryness. The crude material was purified by flashchromatography (0% to 50% ethyl acetate in heptane) to give the titlecompound as a light yellow liquid (62 mg, 65%). MS (ESI): m/z=307.3[M−H]⁻.

The following intermediates were prepared in analogy to intermediate B58from 4-chloro-2-iodo-5-methylphenol (Intermediate B1, step 3) and thecorresponding building blocks indicated in the table below:

Inter- Building block/ mediate Systematic Name intermediate MS, m/z B554-Chloro-2-(5-ethoxy-2- fluorophenyl)-5- methylphenol

5-ethoxy-2- fluorophenylboroni acid CAS: 900174-60-9 MS (ESI): 279.2 [M− H]⁻ B56 4-Chloro-2-(2- methoxyphenyl)-5- methylphenol

(2-methoxyphenyl) boronic acid CAS: 5720-06-9 MS (ESI): 249.2 [M + H]⁺B57 4-Chloro-2-(2-fluoro-5- propan-2-yloxyphenyl)-5- methylphenol

(2-fluoro-5- isopropoxyphenyt) boronic acid CAS: 849062-30-2 MS (ESI):293.2 [M − H]⁻ B59 4-Ch1oro-2-[2-methoxy-5- (trifluoromethyl)phenyl]-5-methylphenol

(2-methoxy-5- (trifluoromethyl)phenyl) boronic acid CAS: 240139-82-6) MS(ESI): 315.2 [M − H]⁻ B60 4-Chloro-2-(2-methoxy-5- propan-2-ylphenyl)-5-methylphenol

(5-isopropyl-2- methoxyphenyl) boronic acid CAS: 216393-63-4) MS (ESI):289.3 [M − H]⁻Intermediate 361

2-Chloro-5-[2-fluoro-5-(morpholine-4-carbonyl)phenyl]-4-hydroxybenzonitrile

Step 1:2-Chloro-5-[2-fluoro-5-(morpholine-4-carbonyl)phenyl]-4-(methoxymethoxy)benzonitrile

The title compound was prepared in analogy to Intermediate B58 from5-bromo-2-chloro-4-methoxymethoxy-benzonitrile (intermediate B32, step2) (100 mg) and (2-fluoro-5-(morpholine-4-carbonyl)phenyl)boronic acid(110 mg, CAS: 1072951-41-7) and was obtained as a light yellow foam (24mg, 15%). MS (ESI): m/z=405.2 [M+H]⁺.

Step 2:2-Chloro-5-[2-fluoro-5-(morpholine-4-carbonyl)phenyl]-4-hydroxybenzonitrile

The title compound was prepared in analogy to Intermediate B39, step 2from2-chloro-5-[2-fluoro-5-(morpholine-4-carbonyl)phenyl]-4-(methoxymethoxy)benzonitrile(29 mg) and was obtained as an off-white solid (14 mg, 54%). MS (ESI):m/z=361.1 [M+H]⁺.

Intermediate B63

3-(5-Chloro-2-hydroxy-4-methylphenyl)-N-cyclopropyl-4-fluoro-N-methylbenzamide

Step 1:3-(5-Chloro-2-methoxy-4-methylphenyl)-N-cyclopropyl-4-fluorobenzamide

The title compound was prepared in analogy to Intermediate B58 from1-chloro-5-iodo-4-methoxy-2-methylbenzene (intermediate B1, step 2) (265mg) and (5-(cyclopropylcarbamoyl)-2-fluorophenyl)boronic acid (251 mg,CAS: 874289-54-0) and was obtained as a yellow solid (163 mg, 52%). MS(ESI): m/z=334.1 [M+H]⁺.

Step 2:3-(5-Chloro-2-methoxy-4-methylphenyl)-N-cyclopropyl-4-fluoro-N-methylbenzamide

Sodium hydride 60% dispersion in mineral oil (37.9 mg) was added to asolution of3-(5-chloro-2-methoxy-4-methylphenyl)-N-cyclopropyl-4-fluorobenzamide(158 mg) in DMF (4.0 mL) at rt under an argon atmosphere. The mixturewas stirred at rt for 45 minutes. Then, iodomethane (87.3 mg) was addeddropwise over a period of 2 minutes and the mixture was stirred at rtfor 3 hours. The reaction mixture was then poured into ice/water. Theaqueous layer was extracted twice with ethyl acetate. The organic layerswere washed once with brine, dried over Na₂SO₄, filtered and evaporatedto dryness. The crude material was purified by flash chromatography (0%to 50% ethyl acetate in heptane) to give the title compound as a whitefoam (154 mg, 93%). MS (ESI): m/z=348.2 [M+H]⁺.

Step 3:3-(5-Chloro-2-hydroxy-4-methylphenyl)-N-cyclopropyl-4-fluoro-N-methylbenzamide

The title compound was prepared in analogy to Intermediate B1, step 3,from3-(5-chloro-2-methoxy-4-methylphenyl)-N-cyclopropyl-4-fluoro-N-methylbenzamide(151 mg) and was obtained as an off-white foam (157 mg, 98%). MS (ESI):m/z=334.1 [M+H]⁺.

Intermediate B62

[3-(5-Chloro-2-hydroxy-4-methylphenyl)-4-fluorophenyl]-pyrrolidin-1-ylmethanone

Step 1: Methyl 3-(5-chloro-2-methoxy-4-methylphenyl)-4-fluorobenzoate

Methyl 3-bromo-4-fluorobenzoate (3.75 g) was dissolved incyclopentylmethylether (70 mL) at room temperature under an argonatmosphere. Then, potassium acetate (6.32 g),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (5.72 g) and[1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) complexwith dichloromethane (526 mg CAS: 95464-05-4) were added to the mixture.The reaction mixture was heated to 95° C. for 4 hours and was thencooled down to rt for another hour. To the mixture was added sodiumcarbonate solution (15%, 26.2 mL),1-chloro-5-iodo-4-methoxy-2-methylbenzene (intermediate B1, step 2)(6.06 g) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with DCM (526 mg, CAS: 95464-05-4). Themixture was heated again to 85° C. for 18 hours. Then, the reactionmixture was cooled to rt and poured into ice/water. The aqueous layerwas extracted twice with cyclopentylmethylether. The organic layers werewashed once with brine, dried over Na₂SO₄, filtered and evaporated todryness. The crude material was purified by flash chromatography (0% to50% ethyl acetate in heptane) to give the title compound as a lightyellow solid (4.46 g, 67%). ¹H NMR (400 MHz, CDCl₃): 2.43 (3H, s), 3.76(3H, s), 3.91 (3H, s), 6.85 (1H, s), 7.14-7.18 (1H, t), 7.24 (1H, s),8.0-8.07 (2H, m).

Step 2: 3-(5-Chloro-2-methoxy-4-methylphenyl)-4-fluorobenzoic acid

LiOH 1M solution (2.51 mL) was added to a solution of methyl3-(5-chloro-2-methoxy-4-methylphenyl)-4-fluorobenzoate (310 mg) in THF(6.0 mL) at room temperature. The mixture was stirred at rt for 18hours. The reaction mixture was poured into ice/water and was acidifiedwith HCl 1M solution to pH=1. The aqueous layer was extracted twice withethyl acetate. The organic layers were washed once with brine, driedover Na₂SO₄, filtered and evaporated to dryness to give the titlecompound as a white solid (309 mg, 99%). MS (ESI): m/z=293.2 [M−H]⁻.

Step 3:[3-(5-Chloro-2-methoxy-4-methylphenyl)-4-fluorophenyl]-pyrrolidin-1-ylmethanone

3-(5-Chloro-2-methoxy-4-methylphenyl)-4-fluorobenzoic acid (100 mg),pyrrolidine (36.2 mg, CAS: 123-75-1) and 4-methylmorpholine (51.5 mg)were dissolved in DMF (4.0 mL) at rt under an argon atmosphere.1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (97.6 mg)and 1-hydroxybenzotriazole hydrate (68.8 mg) were added to the lightyellow solution. The mixture was stirred at rt for 2.5 hours. Thereaction mixture was poured then into ice/water and was basified with 2MNa₂CO₃ solution. The aqueous layer was extracted twice with ethylacetate. The organic layers were washed once with 1M HCl solution andonce with brine, dried over Na₂SO₄, filtered and evaporated to dryness.The crude material was purified by flash chromatography (0% to 70% ethylacetate in heptane) to give the title compound as a white solid (78 mg,65%). MS (ESI): m/z=348.1 [M+H]⁺.

Step 4:[3-(5-Chloro-2-hydroxy-4-methylphenyl)-4-fluorophenyl]-pyrrolidin-1-ylmethanone

The title compound was prepared in analogy to Intermediate B, step 3from[3-(5-chloro-2-methoxy-4-methylphenyl)-4-fluorophenyl]-pyrrolidin-1-ylmethanone(74 mg) and was obtained as an off-white solid (83 mg, 99%). MS (ESI):m/z=334.2 [M+H]⁺.

The following intermediates were obtained in analogy to IntermediateB62, by replacing pyrrolidine with the appropriate amine building blockin Step 3 as indicated in the table below:

Inter- Building block/ mediate Systematic Name intermediate MS, m/z B643-(5-Chloro-2-hydroxy-4- methylphenyl)-4-fluoro-N-(2- hydroxyethyl)-N-methytbenzamide

2-(methylamino)ethanol CAS: 109-83-1 MS (ESI): 338.1 [M + H]⁺ B654-[3-(5-Chloro-2-hydroxy-4- methylphenyl)-4- fluorobenzoyl]-1-methylpiperazin-2-one

1-methylpiperazin-2-one CAS: 59702-07-7 MS (ESI): 377.2 [M + H]⁺ B664-[3-(5-Chloro-2-hydroxy-4- methylphenyl)-4- fluorobenzoyl]-1-methylpiperazin-2-one

N-methylcyclopentan- amine CAS: 2439-56-7 MS (ESI): 362.2 [M + H]⁺ B683-(5-Chloro-2-hydroxy-4- methylphenyl)-4-fluoro-N- methyl-N-(thiophen-2-ylmethyl)benzamide

N-methyl-1-(thiophen-2- yl)methanamine CAS: 58255-18-8 MS (ESI): 390.1[M + H]⁺ B69 [3-(5-Chloro-2-hydroxy-4- methylphenyl)-4-fluorophenyl]-piperidin-1- ylmethanone

piperidine CAS: 110-89-4 MS (ESI): 348.2 [M + H]⁺. B703-(5-Chloro-2-hydroxy-4- methylphenyl)-N- (cyclopropylmethyl)-4-fluoro-N-methylbenzamide

1-cyclopropyl-N- methylmethanamine CAS: 18977-45-2 MS (ESI): 348.1 [M +H]⁺ B71 3-(5-Ch1oro-2-hydroxy-4- methylphenyl)-4-fluoro-N-methyl-N-(pyridin-2- ylmethyl)benzamide

N-methyl-1-(pyridin-2- yl)methanamine CAS: 21035-59-6 MS (ESI): 385.1[M + H]⁺Intermediate B67

4-Chloro-2-[2-fluoro-5-(oxolan-3-ylmethoxy)phenyl]-5-methylphenol

Step 1: 3-[(3-Bromo-4-fluorophenoxy)methyl]oxolane

Diisopropylazodicarboxylate (1.22 g) was added dropwise over a period of5 minutes to a solution of 3-bromo-4-fluorophenol (1.05 g, CAS:27407-11-0), (tetrahydrofuran-3-yl)methanol (674 mg, CAS: 15833-61-1)and triphenylphosphine (1.87 g) in THF (12 mL) at 0° C. under an argonatmosphere. The yellow solution was warmed up to rt and kept at thistemperature for 4.5 hours. The reaction mixture was poured intoice/water and was basified with 2M NaOH solution to achieve pH=10. Theaqueous layer was extracted twice with ethyl acetate. The organic layerswere washed once with brine, dried over Na₂SO₄, filtered and evaporatedto dryness. The crude material was purified by flash chromatography (0%to 60% ethyl acetate in heptane) to give the title compound as a lightyellow liquid (1.26 g, 79%). MS (E): m/z=274.0 [M]⁺.

Step 2:2-[2-Fluoro-5-(oxolan-3-ylmethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

A mixture of 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(129 mg), 3-[(3-bromo-4-fluorophenoxy)methyl]oxolane (100 mg), potassiumacetate (107 mg) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (14.8 mg, CAS:95464-05-4) in 1,4-dioxane (4.0 mL) were purged three times with argonand was then heated to 85° C. for 20 hours under an argon atmosphere.The reaction mixture was cooled down to rt and poured then intoice/water. The aqueous layer was extracted twice with ethyl acetate. Theorganic layers were washed once with brine, dried over Na₂SO₄, filteredand evaporated to dryness. The crude material was purified by flashchromatography (0% to 20% ethyl acetate in heptane) to give the titlecompound as a colorless liquid (90 mg, 62%, purity approx. 80%). MS(EI): m/z=322.0 [M]⁺.

Step 3:4-Chloro-2-[2-fluoro-5-(oxolan-3-ylmethoxy)phenyl]-5-methylphenol

The title compound was prepared in analogy to Intermediate B58 from4-chloro-2-iodo-5-methylphenol (Intermediate B1, step 3) (58 mg) and2-[2-fluoro-5-(oxolan-3-ylmethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(83.5 mg) and was obtained as alight yellow oil (29 mg, 39%). MS (ESI):m/z=337.11 [M+H]⁺.

The following intermediates were obtained in analogy to IntermediateB67, by replacing (tetrahydrofuran-3-yl)methanol in step 1 with theappropriate alcohol building block as indicated in the table below:

Inter- Building block/ mediate Systematic Name intermediate MS, m/z B724-Chloro-2-[2-fluoro-5-(oxan- 4-ylmethoxy)phenyl]-5- methylphenol

(tetrahydro-2H- pyran-4- yl)methanol CAS: 14774-37-9 MS (ESI): 351.1[M + H]⁺ B74 4-Chloro-2-[2-fluoro-5-(oxan- 4-ylmethoxy)phenyl]-5-methylphenol

(tetrahydrofuran-2- ylmethanol CAS: 97-99-4 MS (ESI): 335.2 [M − H]⁻Intermediate B75

2-[3-(5-Chloro-2-hydroxy-4-methylphenyl)-4-fluorophenoxy]-N,N-dimethylacetamide

Step 1: 2-(3-Bromo-4-fluorophenoxy)-N,N-dimethylacetamide

3-Bromo-4-fluorophenol (500 mg, CAS 27407-11-0),2-chloro-N,N-dimethylacetamide (573 mg) and potassium carbonate (832 mg)were combined with acetone (15 mL) at rt under an argon atmosphere. Themixture was heated to reflux for 18 hours and was then kept at rt for 1hour. The reaction mixture was poured then into ice/water and theaqueous layer was extracted twice with ethyl acetate. The organic layerswere washed once with brine, dried over Na₂SO₄, filtered and evaporatedto dryness. The crude material was purified by flash chromatography (0%to 80% ethyl acetate in heptane) to give the title compound as alightyellow liquid (934 mg, 91%, purity approx. 70%). MS (ESI): m/z=278.1[M+H]⁺.

Step 2:2-[4-Fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxyl]-N,N-dimethylacetamide

The title compound was prepared in analogy to Intermediate B67, step 2from 2-(3-bromo-4-fluorophenoxy)-N,N-dimethylacetamide (930 mg) and wasobtained as a colorless oil (188 mg, 18%, purity 70%). MS (ESI):m/z=324.2 [M+H]⁺.

Step 3:2-[3-(5-Chloro-2-hydroxy-4-methylphenyl)-4-fluorophenoxy]-N,N-dimethylacetamide

The title compound was prepared in analogy to Intermediate B58 from4-chloro-2-iodo-5-methylphenol (intermediate B1, step 3) (108 mg) and2-[4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-N,N-dimethylacetamide(186 mg, purity 70%) and was obtained as a light brown foam (63 mg,46%). MS (ESI): m/z=338.1 [M+H]⁺.

Intermediate B73

3-(5-Chloro-2-hydroxy-4-methylphenyl)-4-fluoro-N-(2-methoxyethyl)-N-methylbenzamide

Step 1: 3-(5-Chloro-2-hydroxy-4-methylphenyl)-4-fluorobenzoic acid

3-(5-Chloro-2-methoxy-4-methylphenyl)-4-fluorobenzoic acid (IntermediateB62, step 2) (145 mg) was combined with dichloromethane (5.0 mL) at 0°C. under an argon atmosphere. Then, boron tribromide 1M solution indichloromethane (1.23 mL) was added dropwise over a period of 2 minutes.The resulting yellow solution was then kept at rt for 6 hours. Thereaction mixture was poured then into ice/water and the aqueous layerwas extracted twice with ethyl acetate. The organic layers were washedonce with brine, dried over Na—SO₄, filtered and evaporated to drynessto give the title compound as a light brown solid (146 mg, 100%). MS(ESI): m/z=559.21 [2M−H]⁻.

Step 2:3-(5-Chloro-2-hydroxy-4-methylphenyl)-4-fluoro-N-(2-methoxyethyl)-N-methylbenzamide

The title compound was obtained in analogy to Intermediate B62, step 3from 3-(5-chloro-2-hydroxy-4-methylphenyl)-4-fluorobenzoic acid (50 mg)using 2-methoxy-N-methylethanamine (24 mg, CAS: 38256-93-8) in place ofpyrrolidine and was obtained as a white foam (40 mg, 63%). MS (EST):m/z=352.1 [M+H]⁺.

Intermediate B76

1-[[3-(5-Chloro-2-hydroxy-4-methylphenyl)-4-fluorophenyl]methyl]-4-methylpiperazine-2,5-dione

Step 1: 2-Bromo-4-(bromomethyl)-1-fluorobenzene

Tetrabromomethane (7.28 g) was added to a solution of3-bromo-4-fluorophenyl)methanol (3.0 g, CAS: 77771-03-0) in THF (50 mL)at 0° C. under an argon atmosphere. Then, a solution oftriphenylphosphine (5.76 g) in THF (30 mL) was added dropwise over aperiod of 40 minutes. The mixture was warmed up to rt and kept at thistemperature for 65 hours. The reaction mixture was poured then intoice/water and was extracted two times with ethyl acetate. The organiclayers were washed once with brine, dried over Na₂SO₄, filtered andevaporated to dryness. The crude material was purified by flashchromatography (0% to 10% ethyl acetate in heptane) to give the titlecompound as a light yellow liquid (5.10 g, 95%, purity 70%). MS (EI):m/z=267.9 [M]⁺.

Step 2: 1-[(3-Bromo-4-fluorophenyl)methyl]-4-methylpiperazine-2,5-dione

1-Methylpiperazine-2,5-dione (150 mg, CAS: 5625-52-5) was dissolved inDMF (5.0 mL) at rt under an argon atmosphere. The mixture was cooleddown to 0° C. and sodium hydride 60% dispersion in mineral oil (103 mg)was added in one portion. The suspension was stirred at 0° C. for 10minutes and then warmed up to rt for 45 minutes. Then,2-bromo-4-(bromomethyl)-1-fluorobenzene (627 mg) was added dropwise overa period of 5 minutes. The mixture was stirred at rt for 16 hours. Thereaction mixture was poured then into ice/water and the aqueous layerwas extracted twice with ethyl acetate. The organic layers were washedonce with brine, dried over Na₂SO₄, filtered and evaporated to dryness.The crude material was purified by flash chromatography (0% to 10%methanol in dichloromethane) to give the title compound as a light browngum (121 mg, 32%). MS (ESI): m/z=315.0 [M+H]⁺.

Step 3:1-[[4-Fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-4-methylpiperazine-2,5-dione

The title compound was prepared in analogy to Intermediate B67, step 2,from 1-[(3-bromo-4-fluorophenyl)methyl]-4-methylpiperazine-2,5-dione(120 mg) and was obtained as a light brown gum (102 mg, 52%, purity70%). MS (ESI): m/z=363.2 [M+H]⁺.

Step 4:1-[[3-(5-Chloro-2-hydroxy-4-methylphenyl)-4-fluorophenyl]methyl]-4-methylpiperazine-2,5-dione

The title compound was prepared in analogy to Intermediate B58 from4-chloro-2-iodo-5-methylphenol (intermediate B1, step 3) (52 mg) and1-[[4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-4-methylpiperazine-2,5-dione(100 mg, purity ˜70%) and was obtained as a light brown foam (28 mg,37%). MS (ESI): m/z=377.1 [M+H]⁺.

The following intermediates were obtained in analogy to intermediateB76, by replacing 1-methylpiperazine-2,5-dione in Step 2 with theappropriate amide building block as indicated in the table below:

Inter- Building block/ mediate Systematic Name intermediate MS, m/z B811-[[3-(5-Chloro-2-hydroxy-4- methylphenyl)-4- fluorophenyl]methyl]pyrrolidin-2-one

pyrrolidin-2-one CAS: 616-45-5 MS (ESI): 334.0 [M + H]⁺ B823-[[3-(5-Chloro-2-hydroxy-4- methylphenyl)-4- fluorophenyl]methyl]-1,3-oxazolidin-2-one

oxazolidin-2-one CAS: 497-25-6 MS (EST): 334.1 [M − H]⁻Intermediate 878

N-[[3-(5-Chloro-2-hydroxy-4-methylphenyl)-4-fluorophenyl]methyl]-2-methoxy-N-methylacetamide

Step 1: N-[(3-Bromo-4-fluorophenyl)methyl]-2-methoxyacetamide

2-Methoxyacetic acid (165 mg, CAS: 625-45-6),(3-bromo-4-fluorophenyl)-methanamine hydrochloride (529 mg, CAS:202865-68-7) and 4-methylmorpholine (741 mg) were dissolved in DMF (6.0mL) at rt under an argon atmosphere.1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (527 mg) and1-hydroxybenzotriazole hydrate (371 mg) were added to the light yellowsolution. The mixture was stirred at rt for 16 hours. The reactionmixture was poured then into ice/water and was basified with 2M Na₂CO₃solution. The aqueous layer was extracted twice with ethyl acetate. Theorganic layers were washed once with brine, dried over Na₂SO₄, filteredand evaporated to dryness. The crude material was purified by flashchromatography (0% to 80% ethyl acetate in heptane) to give the titlecompound as a white solid (503 mg, 98%). MS (ESI): m/z=278.01 [M+H]⁺.

Step 2: N-[(3-Bromo-4-fluorophenyl)methyl]-2-methoxy-N-methylacetamide

The title compound was prepared in analogy to Intermediate B63, step 2,from N-[(3-bromo-4-fluorophenyl)methyl]-2-methoxyacetamide (290 mg) andwas obtained as a colorless liquid (198 mg, 62%). MS (ESI): m/z=290.0[M+H]⁺.

Step 3:N-[[4-Fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-2-methoxy-N-methylacetamide

The title compound was prepared in analogy to Intermediate B67, step 2,from N-[(3-bromo-4-fluorophenyl)methyl]-2-methoxy-N-methylacetamide (199mg) and was obtained as a light yellow liquid (262 mg, 57%, purity˜50%). MS (ESI): m/z=338.2 [M+H]⁺.

Step 4:N-[[3-(5-Chloro-2-hydroxy-4-methylphenyl)-4-fluorophenyl]methyl]-2-methoxy-N-methylacetamide

The title compound was prepared in analogy to Intermediate B58 from4-chloro-2-iodo-5-methylphenol (intermediate B1, step 3) (102 mg) andN-[[4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-2-methoxy-N-methylacetamide(256 mg, purity ˜50%) and was obtained as a yellow gum (106 mg, 64%,purity ˜80%). MS (ESI): m/z=352.1 [M+H]⁺.

The following intermediates were obtained in analogy to intermediateB78, by replacing 2-methoxyacetic acid in Step 1 with the appropriatecarboxylic acid building block as indicated in the table below:

Inter- Building block/ mediate Systematic Name intermediate MS, m/z B80N-[[3-(5-Chloro-2-hydroxy-4- methylphenyl)-4- fluorophenyl]methyl]-N-methylcyclopropane carboxamide

cyclopropanecarboxylic acid CAS: 1759-53-1 MS (EST): 348.1 [M + H]⁺Intermediate B79

N-[[3-(5-Chloro-2-hydroxy-4-methylphenyl)-4-fluorophenyl]methyl]cyclopropanecarboxamide

Step 1: N-[(3-Bromo-4-fluorophenyl)methyl]cyclopropanecarboxamide

The title compound was prepared in analogy to Intermediate B78, step 1,from cyclopropanecarboxylic acid (127 mg, CAS: 1759-53-1) and wasobtained as a white powder (444 mg, 100%). MS (ESI): m/z=272.0 [M+H]⁺.

Step 2:N-[[4-Fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-cyclopropanecarboxamide

The title compound was prepared in analogy to Intermediate B67, step 2,from N-[(3-bromo-4-fluorophenyl)methyl]cyclopropanecarboxamide (217 mg)and was obtained as a light yellow oil (257 mg, 61%, purity 60%). MS(ESI): m/z=320.2 [M+H]⁺.

Step 3:N-[[3-(5-Chloro-2-hydroxy-4-methylphenyl)-4-fluorophenyl]methyl]cyclopropanecarboxamide

The title compound was prepared in analogy to intermediate B58 from4-chloro-2-iodo-5-methylphenol (intermediate B1, step 3) (119 mg) andN-[[4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-cyclopropanecarboxamide(236 mg, purity ˜60%) and was obtained as a light yellow foam (63 mg,42%). MS (ESI): m/z=334.1 [M+H]⁺.

The following intermediates were obtained in analogy to intermediateB79, by replacing cyclopropanecarboxylic acid in step 1 with theappropriate carboxylic acid building block as indicated in the tablebelow:

Inter- Building block/ mediate Systematic Name intermediate MS, m/z B83N-[[3-(5-Chloro-2-hydroxy-4- methylphenyl)-4- fluorophenyl]methyl]-2-methoxyacetamide

2-methoxyacetic acid CAS: 625-45-6 MS (ESI): 336.1 [M − H]⁻Intermediate B77

7-(5-Chloro-2-hydroxy-4-methylphenyl)-6-fluoro-3-methyl-1,3-benzoxazol-2-one

Step 1: 7-Bromo-6-fluoro-3H-1,3-benzoxazol-2-one

A solution of 1,1′-carbonyldiimidazole (378 mg) in tetrahydrofuran (6.0mL) was added to a suspension of 6-amino-2-bromo-3-fluorophenol (400 mg,CAS: 1257535-00-4) in THF (5.0 mL) at rt under an argon atmosphere. Themixture was stirred at rt for 4 hours. The reaction mixture was pouredthen into ice/water and the aqueous layer was extracted twice with ethylacetate. The organic layers were washed once with brine, dried overNa₂SO₄, filtered and evaporated to dryness. The crude material waspurified by flash chromatography (0% to 100% ethyl acetate in heptane)to give the title compound as an orange solid (298 mg, 65%). MS (ESI):m/z=230.0 [M−H]⁻.

Step 2: 7-Bromo-6-fluoro-3-methyl-1,3-benzoxazol-2-one

The title compound was prepared in analogy to Intermediate B63, step 2,from 7-bromo-6-fluoro-3H-1,3-benzoxazol-2-one (290 mg) and was obtainedas a light brown foam (263 mg, 84%). MS (EI): m/z=245.0 [M]⁺.

Step 3:2-(5-Chloro-2-methoxy-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

The title compound was prepared in analogy to Intermediate B67, step 2,from 1-chloro-5-iodo-4-methoxy-2-methylbenzene (Intermediate B1, step 2)(300 mg) and was obtained as an off-white solid (75 mg, 21%, purity˜80%). MS (ESI): m/z=311.1 [M+H]⁺.

Step 4:7-(5-Chloro-2-methoxy-4-methylphenyl)-6-fluoro-3-methyl-1,3-benzoxazol-2-one

The title compound was prepared in analogy to Intermediate B58 from7-bromo-6-fluoro-3-methyl-1,3-benzoxazol-2-one (Intermediate B77, step2) (38 mg) and2-(5-chloro-2-methoxy-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(71 mg, purity ˜80%) and was obtained as an off-white solid (18 mg,36%). MS (ESI): m/z=322.0 [M+H]⁺.

Step 5:7-(5-Chloro-2-hydroxy-4-methylphenyl)-6-fluoro-3-methyl-1,3-benzoxazol-2-one

The title compound was prepared in analogy to Intermediate B1, step 3,from7-(5-chloro-2-methoxy-4-methylphenyl)-6-fluoro-3-methyl-1,3-benzoxazol-2-one(18 mg) and was obtained as a light brown solid (15 mg, 79%, purity90%). MS (ESI): m/z=306.1 [M−H]⁻.

Intermediate B86

3-(5-Chloro-2-hydroxy-4-methylphenyl)-4-(trifluoromethoxy)benzonitrile

Cyclopentyl methyl ether (5 mL) was purged three times with argon andwas then combined with 3-bromo-4-(trifluoromethoxy)benzonitrile (130 mg,CAS: 191602-89-8), potassium acetate (144 mg),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (130 mg) and[1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) DCM complex(20 mg). The mixture was heated to 95° C. for 4 hours under an argonatmosphere. The reaction mixture was allowed to cool to rt and was thencombined with argon-purged sodium carbonate solution (15% in water, 600μL), 4-chloro-2-iodo-5-methylphenol (131 mg, obtained in IntermediateB1, step 3) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(I) DCM complex (20 mg). The reaction mixture was againheated to 86° C. for 18 hours. The reaction mixture was cooled to rt andwas poured then into ice/water. The aqueous layer was extracted twicewith ethylacetate and the organic layers were washed once with brine,dried over Na₂SO₄, filtered and evaporated. The residue was purified byflash chromatography (silica gel, 20 g cartridge, gradient of 0% to 20%ethyl acetate in heptane) to provide the title compound as alight yellowsolid (48 mg). MS (ESI⁻): m/z=326.3 [M−H]⁻.

The following intermediates were made in analogy to Intermediate B86 byreplacing 3-bromo-4-(trifluoromethoxy)benzonitrile with thecorresponding aryl-bromide and, if appropriate,4-chloro-2-iodo-5-methylphenol with the corresponding aryl-iodide asdescribed in the following table:

Inter- Building block/ mediate Systematic Name intermediate MS, m/z B882-chloro-5-(2-fluoro-3- methoxyphenyl)-4- hydroxybenzonitrile

1-bromo-2-fluoro-3- methoxybenzene (CAS: 95970-22-2) and2-chloro-4-hydroxy-5- iodobenzonitrile (Intermediate B31, Method B,step 1) MS (ESI): 278.1 [M + H]⁺ B90 4-chloro-2-(2-fluoro-3-methoxyphenyl)-5- methylphenol

1-bromo-2-fluoro-3- methoxybenzene (CAS: 95970-22-2) and4-chloro-2-iodo-5- methylphenol (Intermediate B1, step 3) MS (ESI):267.1 [M + H]⁺ B91 2-chloro-5-(2,3- difluorophenyl)-4-hydroxybenzonitrile

1-bromo-2,3- difluorobenzene (CAS: 38573-88-5) and 2-chloro-4-hydroxy-5-iodobenzonitrile (Intermediate B31, Method B. step 1) MS (ESI⁻): 264.1[M − H]⁻ B92 4-chloro-2-(5- cyclopropyloxy-2-fluorophenyl)-5-methylphenol

2-bromo-4- cyclopropyloxy-1- fluorobenzene (CAS: 1243469-64-8) and4-chloro-2-iodo-5- methylphenol (Intermediate B1, step 3) MS (ESI):293.1 [M + H]⁺ B93 2-chloro-5-(5-chloro-2- fluorophenyl)-4-hydroxybenzonitrile

2-bromo-4-chloro-1- fluorobenzene (CAS: 1996-30-1) and2-chloro-4-hydroxy-5- iodobenzonitrile (Intermediate B31, Method B,step 1) MS (ESI⁻): 280.1 [M − H]⁻ B94 2-chloro-5-(2,5-difluorophenyl)-4- hydroxybenzonitrile

2-bromo-1,4- difluorobenzene (CAS: 399-94-0) and 2-chloro-4-hydroxy-5-iodobenzonitrile (Intermediate B31, Method B. step 1) MS (ESI⁻): 264.1[M + H]⁻ B95 2-chloro-5-(5- cyclopropyloxy-2- fluorophenyl)-4-hydroxybenzonitrile

2-bromo-4- cyclopropyloxy-1- fluorobenzene (CAS: 1243469-64-8) and2-chloro-4-hydroxy-5- iodobenzonitrile (Intermediate B31, Method B,step 1) MS (ESI⁻): 302.2 [M − H]⁻ B96 2-chloro-5-[2-fluoro-5-(trifluoromethyl)phenyl]-4- hydroxybenzonitrile

2-bromo-1-fluoro-4- trifluoromethyl)benzene (CAS: 68322-84-9) and2-chloro-4-hydroxy-5- iodobenzonitrile (Intermediate B31, Method B,step 1) MS (ESI⁻): 314.2 [M − H]⁻Intermediate B87

2-Chloro-5-[2-fluoro-5-(oxolan-2-ylmethoxy)phenyl]-4-hydroxybenzonitrile

This material was prepared in analogy to Intermediate B67, steps 1-3, byreplacing in step 1 (tetrahydrofuran-3-yl)methanol with(tetrahydrofuran-2-yl)methanol (CAS: 97-99-4), and in step 34-chloro-2-iodo-5-methylphenol with2-chloro-4-hydroxy-5-iodobenzonitrile (made in Intermediate B31, MethodB, step 1). Light brown oil: MS (ESI): 348.11 [M+H]⁺.

Intermediate B97

2-Chloro-5-[2-fluoro-5-(trifluoromethoxy)phenyl]-4-hydroxybenzonitrile

This material was made in analogy to Intermediate B86 from2-bromo-1-fluoro-4-(trifluoromethoxy)benzene (210 mg, CAS: 286932-57-8)and 2-chloro-4-hydroxy-5-iodobenzonitrile (204 mg, Intermediate B31,Method B, Step 1) to provide the title compound as a colorless solid(130 mg, 47%). MS (m/z): 330.1 [M−H]⁻.

Intermediate B98

2-Chloro-5-[2-fluoro-5-(2,2,2-trifluoroethoxy)phenyl]-4-hydroxybenzonitrile

Step 1: 2-Bromo-1-fluoro-4-(2,2,2-trifluoroethoxy)benzene

3-Bromo-4-fluorophenol (500 mg. CAS: 27407-11-0),1,1,1-trifluoro-2-iodoethane (824 mg, CAS: 353-83-3) and potassiumcarbonate (1.09 g) were combined with DMF (10.0 mL) at room temperatureunder an argon atmosphere. The mixture was heated to 80° C. for 2 hoursand then at 60° C. for another 16 hours. TLC showed a lot of startingmaterial. More 1,1,1-trifluoro-2-iodoethane (824 mg) and potassiumcarbonate (724 mg) were added and the mixture was heated again at 80° C.for 64 hours. The reaction mixture was then cooled and poured intoice/water. The aqueous layer was basified with sat. Na₂CO₃ solution andwas extracted twice with ethyl acetate. The organic layers were washedonce with brine, dried over Na₂SO₄, filtered and evaporated. ResidualDMF was removed by co-evaporation with toluene. The crude material waspurified by flash chromatography (ISCO, silica gel, 25 g cartridge, 0%to 20% ethyl acetate in heptane) to give the title compound as a lightyellow liquid (601 mg, 80%). MS (EI, m/z): 272.0 [M]⁺.

Step 2:2-Chloro-5-[2-fluoro-5-(2,2,2-trifluoroethoxy)phenyl]-4-hydroxybenzonitrile

This material was made in analogy to Intermediate B86 from2-bromo-1-fluoro-4-(2,2,2-trifluoroethoxy)benzene (220 mg) and2-chloro-4-hydroxy-5-iodobenzonitrile (203 mg, Intermediate B31, MethodB, Step 1) to provide the title compound as an off-white solid (8 mg,3%). (MS (m/z): 346.1 [M+H]⁺.

Intermediates C

Intermediate C3

4-Chloro-5-fluoro-2-isopropyl-phenol

Step 1: 4-Chloro-5-fluoro-2-isopropenyl-phenol

To a solution of 4-chloro-5-fluoro-2-iodo-phenol (500 mg, CAS:1235407-15-4) in DMF (8 mL) were added isopropenylboronic acid pinacolester (771 mg, CAS: 126726-62-3) and K₂CO₃ (761 mg) and the reactionmixture was purged with argon for 30 min. Then Pd(dppf)Cl₂ DCM complex(45 mg, CAS: 14221-01-3) was added and the reaction mixture was stirredat 90° C. for 16 hours. The solvent was evaporated, the residue wasdiluted with H₂O (40 mL) and extracted with EtOAc (3×25 mL). Thecombined organic layers were washed with brine (30 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Thecrude material was purified by flash chromatography over silica gel(2-4% EtOAc/hexane) to give the title compound as a colorless liquid(263 mg, 76%). ¹H-NMR (400 MHz, CDCl₃) 2.07 (3H, s), 5.15 (1H, s), 5.42(1H, s), 5.73 (1H, bs), 6.73 (1H, d, J=8), 7.12 (1H, d, J=8).

Step 2: 4-Chloro-5-fluoro-2-isopropyl-phenol

A solution of 4-chloro-5-fluoro-2-isopropenyl-phenol (524 mg) in MeOH(30 mL) was purged with argon for 15 min. Then, 10% palladium on carbon(130 mg, CAS: 7440-05-3) was added and the reaction mixture was purgedwith argon for another 5 min. The reaction mixture was stirred underhydrogen (balloon) for 16 hours at rt. The reaction mixture was filteredthrough a celite bed, the celite bed was washed with EtOAc (20 mL) andthe filtrate was evaporated to give the title compound as a green liquid(513 mg, 97%). ¹H-NMR (400 MHz, CDCl₃) 1.25 (6H, m), 3.07-3.14 (1H, m),4.99 (1H, s), 6.58 (1H, d, J=12), 7.13 (1H, d, J=8).

Intermediate C4:

5-Chloro-2-isopropyl-4-methyl-phenol Step 1:1-Chloro-4-iodo-5-methoxy-2-methyl-benzene

The title compound was obtained in analogy to Intermediate A14, step 5,from 4-chloro-2-methoxy-5-methyl-phenylamine (CAS: 62492-42-6) as abrown liquid. ¹H-NMR (400 MHz, CDCl₃): 2.25 (3H, s), 3.83 (3H, s), 6.79(1H, s), 7.60 (1H, s).

Step 2: 5-Chloro-2-iodo-4-methyl-phenol

The title compound was obtained in analogy to Intermediate B1, step 3,from 1-chloro-4-iodo-5-methoxy-2-methyl-benzene as a yellow liquid.¹H-NMR (400 MHz, CDCl₃): 2.25 (3H, s), 5.17 (1H, s), 6.99 (1H, s), 7.49(1H, s).

Step 3: 5-Chloro-2-isopropenyl-4-methyl-phenol

The title compound was obtained in analogy to Intermediate C3, step 1,from 5-chloro-2-iodo-4-methyl-phenol and isopropenylboronic acid pinacolester (CAS: 126726-62-3) as a yellow liquid. ¹H-NMR (400 MHz, CDCl₃):2.20 (3H, s), 2.26 (3H, s) 5.10 (1H, s), 5.38 (1H, s), 6.93 (1H, s),6.94 (1H, s).

Step 4: 5-Chloro-2-isopropyl-4-methyl-phenol

The title compound was obtained in analogy to Intermediate C3, step 2,from 5-chloro-2-isopropenyl-4-methyl-phenol by hydrogenation as acolorless liquid. ¹H-NMR (400 MHz CDCl₃) 1.22 (6H, m), 2.27 (3H, s),3.08-3.11 (1H, m), 4.63 (1H, s), 6.75 (1H, s), 6.93 (1H, s).

Intermediate C9:

2-(5-Chloro-2-hydroxy-4-methyl-phenyl)-2-methyl-propionitrile

Step 1: 4-Chloro-2-fluoro-5-methyl-phenol

To a solution of 2-fluoro-5-methyl-phenol (5.0 g, CAS: 63762-79-8) inAcOH (50 mL) were added NCS (5.82 g, CAS: 128-09-6) and triflic acid(1.76 mL, CAS: 1493-13-6) and the reaction mixture was refluxed for 24hours. The solvent was evaporated under reduced pressure and thecompound was purified by flash chromatography over silica gel (40-50%EtOAc/hexane) to get the title compound as a colorless liquid (3.5 g,55%). ¹H-NMR (400 MHz, CDCl₃): 2.26 (3H, s), 6.85 (1H, d, J=8), 7.07(1H, d, J=8).

Step 2: 1-Benzyloxy-4-chloro-2-fluoro-5-methyl-benzene

To a stirred solution of 4-chloro-2-fluoro-5-methyl-phenol (3.25 g) inCH₃CN (50 mL) were added Cs₂CO₃ (13.19 g, CAS: 534-17-8) and benzylbromide (2.66 mL, CAS: 100-39-0) and the reaction mixture was refluxedfor 2 hours. The reaction mixture was filtered through a celite bed andthe filtrate was evaporated. The compound was purified by columnchromatography (10% EtOAc/hexane) to give the title compound as a whitesolid (3.94 g, 78%). ¹H-NMR (400 MHz, CDCl₃): 2.27 (3H, s), 5.09 (2H,s), 6.85 (1H, d, J=8), 7.09 (1H, d, J=12), 7.30-7.42 (5H, m).

Step 3: 2-(2-Benzyloxy-5-chloro-4-methyl-phenyl)-2-methyl-propionitrile

To a stirred solution of 1-benzyloxy-4-chloro-2-fluoro-5-methyl-benzene(1.0 g) in anhydrous toluene (10 mL) in a sealed tube were addedisobutyronitrile (1.43 mL, CAS: 78-82-0) and KHMDS (6 mL, CAS:40949-94-8, 1M solution in toluene) and the reaction mixture was stirredat 60° C. for 12 hours. The reaction mixture was poured into H₂O (20 mL)and extracted with EtOAc (2×30 mL). The combined organic extract wasdried over Na₂SO₄ and evaporated under reduced pressure. The compoundwas purified by flash chromatography over silica gel (3-20%EtOAc/hexane) to give the title compound as a brown solid (167 mg, 14%).¹H-NMR (400 MHz, CDCl₃): 1.74 (6H, s), 2.32 (3H, s), 5.15 (2H, s), 6.85(1H, s), 7.28 (1H, s), 7.31-7.51 (5H, m).

Step 4: 2-(5-Chloro-2-hydroxy-4-methyl-phenyl)-2-methyl-propionitrile

To a stirred solution of2-(2-benzyloxy-5-chloro-4-methyl-phenyl)-2-methyl-propionitrile (420 mg)in dry DCM (20 mL) at −78° C. was added BCl₃ (2.8 mL, 1M solution inDCM, CAS: 10294-34-5) and the reaction mixture was stirred at 25° C. for4 hours. The reaction mixture was quenched with saturated aqueous Na₂CO₃solution and was extracted with DCM (2×20 mL). The combined organiclayers were dried over Na₂SO₄, filtered and evaporated under reducedpressure. The residue was purified by flash chromatography over silicagel (0-10% EtOAc/hexane) to give the title product as a brown solid (50mg, some impurities). ¹H-NMR (400 MHz, CDCl₃): 1.76 (6H, s), 2.28 (3H,s), 6.57 (1H, s), 7.29 (1H, s).

Intermediate C1-A:

3-Chloro-6-[(4-chloro-2-isopropyl-5-methyl-phenoxy)methyl]pyridazine

To a solution of 3-chloro-6-chloromethyl-pyridazine (81 mg, CAS:120276-59-7) in acetone (5 mL) was added4-chloro-2-isopropyl-5-methyl-phenol (92 mg, CAS: 89-68-9) and K₂CO₃(104 mg) and the reaction mixture was heated at reflux for 16 hours. Thereaction mixture was poured into H₂O (50 mL) and EtOAc (75 mL) and thelayers were separated. The organic layer was washed with H₂O (50 mL),dried over Na₂SO₄, filtered and concentrated in vacuo to give the titlecompound as a light yellow solid (0.072 g, 46%). MS (EST): m/z=311.07[M]⁺.

Intermediate C2-A:

3-Chloro-6-(4-chloro-2-cyclopropyl-5-methyl-phenoxymethyl)-pyridazine

To a solution of 3-chloro-6-chloromethyl-pyridazine (200 mg, CAS:120276-59-7) in CH₃CN (10 mL) were added4-chloro-2-cyclopropyl-5-methyl-phenol (82 mg, Intermediate A19), K₂CO₃(109 mg. CAS: 584-08-7) and tetrabutylammonium iodide (16 mg, CAS:311-28-4) and the reaction mixture was heated to reflux for 16 hours.The solvent was evaporated under reduced pressure and the product waspurified by flash chromatography over silica gel (30-40% EtOAc/hexane)to give the title compound as a yellow solid (48 mg, 35%). ¹H-NMR (400MHz, CDCl₃): 0.61-0.65 (2H, m), 0.90-0.95 (2H, m), 2.07-2.09 (1n, m),2.28 (3H, s), 5.41 (2H, s), 6.73 (1H, s), 6.83 (1H, s), 7.56 (1H, d,J=8), 7.74 (1H, d, J=8). The following intermediates were made inanalogy to Intermediate C2-A from commercial3-chloro-6-chloromethyl-pyridazine (CAS: 120276-59-7) and the properphenol building block as indicated in the following table:

Inter- Building block/ mediate Systematic Name intermediate Analyticaldata C3-A 3-Chloro-6-(4-chloro-5-fluoro- 2-isopropyl-phenoxymethyl)-pyridazine

4-Chloro-5-fluoro-2- isopropyl-phenol Intermediate C3 ¹H-NMR (400 MHz,CDCl₃): 1.22 (6H, m), 3.26-3.29 (1H, m), 5.36 (2H, s), 6.73 (1H, d, J =8), 7.20 (1H, d, J = 8), 7.58 (1H, d, J = 8), 7.65 (1H, d, J = 8). C4-A3-Chloro-6-(5-chloro-2- isopropyl-4-methyl- phenoxymethyl)-pyridazine

5-Chloro-2-isopropyl-4- methyl-phenol Intermediate C4 ¹H-NMR (400 MHz,CDCl₃): 1.22 (6H, m), 2.25 (3H, s), 3.08-3.13 (1H, m), 4.65 (2H, s),4.62 (d, J = 16), 4.76 (d, J = 8), 6.93 (1H, s), 6.99 (1H, s) C5-A3-Chloro-6-(4-chloro-2- cyclobutyl-5-methyl- phenoxymethyl)-pyridazine

4-chloro-2-cyclobutyl- 5-methyl-phenol Intermediate A31 ¹H-NMR (400 MHz,CDCl₃): 1.82-1.86 (1H, m), 1.98-2.16 (4H, m), 3.66-3.72 (5H, m), 5.35(2H, s), 6.70 (1H, s), 7.17 (1H, s), 7.56 (1H, d, J = 8), 7.65 (1H, d, J= 8) C6-A 3-Chloro-6-(4-chloro-2- cyclohexyl-5-methyl-phenoxymethyl)-pyridazine

4-chloro-2-cyclohexyl- 5-methyl-phenol Intermediate A20 ¹H-NMR (400 MHz,CDCl₃): 1.24-1.42 (7H, m), 1,82-1.83 (3H, m), 2.88-2.92 (1H, m), 5.38(2H, s) , 6.72 (1H, s), 7.15 (1H, s), 7.57 (1H, d, J = 8), 7.67 (1H, d,J = 8). C7-A 3-Chloro-6-[4-chloro-5- methyl-2-(tetrahydro-pyran-4-yl)-phenoxymethyl]-pyridazine

4-chloro-5-methyl-2- tetrahydro-pyran-4-yl)- phenol Intermediate A21¹H-NMR (400 MHz, CDCl₃): 1.70-1.84 (4H, m), 2.30 (3H, s), 3.11- 3.16(1H, m), 3.48-3.54 (2H, m), 4.05-4.08 (2H, 5.40 (2H, s), 6.75 (1H, s),7.57-7.62 (3H, m). C8-A 3-(2-tert-Butyl-4-chloro-5-methyl-phenoxymethyl)-6- chloro-pyridazine

2-tert-butyl-4-chloro-5- methyl-phenol CAS: 30894-16-7 ¹H-NMR (400 MHz,CDCl₃): 1.37 (9H, s), 2.28 (3H, s), 5.43 (2H, s), 6.74 (1H, s), 7.24(1H, s), 7.56 (IH, d, J = 8), 7,68 (1H, d, J = 8). C9-A2-[5-Chloro-2-(6-chloro- pyridazin-3-ylmethoxy)-4-methyl-phenyl]-2-methyl- propionitrile

2-(5-chloro-2-hydroxy- 4-methyl-phenyl)-2- methyl-propionitrileIntermediate C9 MS (EI): m/z = 337.5 [M + H]⁺

The following intermediates of type C were made in analogy toIntermediate C2-A from commercial 3-chloro-6-chloromethyl-pyridazine(CAS: 120276-59-7) and the proper phenol building block as indicated inthe following table:

Inter- Building block/ mediate Systematic Name intermediate Analyticaldata C10-A 3-chloro-6-[[4-chloro-2-(2- methoxypyridin-3-yl)-5-methylphenoxy]methyl]- pyridazine

4-chloro-2-(2- methoxypyridin-3-yl)- 5-methylphenol Intermediate B53 MS(ESI, m/z): 376.1 [M + H]⁺ C12-A 2-chloro-4-[(6-chloropyridazin-3-yl)methoxy]-5- phenylbenzonitrile

2-chloro-4-hydroxy-5- phenylbenzonitrile Intermediate B31 MS (ESI, m/z):356.1 [M + H]⁺ C13-A 4-tert-butyl-5-[(6-chloro-pyridazin-3-yl)methoxyl-2- methyl-benzonitrile

4-teri-butyl-5-hvdroxy- 2-methylbenzonitrile Intermediate A17 MS (ESI,m/z): 316.2 [M + H]⁺ C14-A 2-chloro-4-[(6-chloropyridazin-3-yl)methoxy]-5-(5-cyclo- propyloxy-2-fluorophenyl)- benzonitrile

2-chloro-5-(5- cyclopropyloxy-2- fluorophenyl)-4- hydroxybenzonitrileIntermediate B95 MS (ESI, m/z): 430.1 [M + H]⁺

Intermediates D

Intermediate D9:

2-tert-Butyl-5-methyl-4-methylsulfonyl-phenol

Step 1: 4-Bromo-2-tert-butyl-5-methyl-phenol

To a solution of 2-tert-butyl-5-methylphenol (1.0 g, CAS: 88-60-8) wasadded N-bromosuccinimide (1.19 g) and the reaction mixture was stirredfor 15 h. The reaction mixture was then poured onto saturated NH₄Clsolution and was extracted with EtOAc. The combined organic layers weredried over Na₂SO₄ and were concentrated in vacuo. The residue waspurified by chromatography (silica gel, 20 g, gradient of EtOAc inheptane) to give the title compound (1.4 g, 93%) as a yellow oil. MS(ESI): m/z=244.2 [M+H]⁺.

Step 2: 1-Benzyloxy-4-bromo-2-tert-butyl-5-methyl-benzene

To a solution of 4-bromo-2-tert-butyl-5-methyl-phenol (1.4 g, in DMF (15mL) was slowly added NaH (302 mg, 55% in mineral oil) and the reactionmixture was stirred for 30 minutes at rt. Then, benzylchloride (765 mg,696 μL) was added and the reaction mixture was stirred for 2 h. Thereaction mixture was poured onto saturated NH₄Cl solution and wasextracted with EtOAc. The combined organic layers were dried over Na₂SO₄and were concentrated in vacuo to afford the title compound (1.9 g, 97%)as white powder which was used in the next reaction step without furthercharacterization.

Step 3: 1-Benzyloxy-2-tert-butyl-5-methyl-4-methylsulfonyl-benzene

To a mixture of 1-benzyloxy-4-bromo-2-tert-butyl-5-methyl-benzene (1.9g), L-proline (525 mg) and copper(I)iodide (869 mg) in DMF (10 mL) wereadded sodium hydroxide (182 mg) and sodium methanesulfinate (1.16 g) andthe reaction mixture was heated to 135° C. in a sealed tube for 15 h.The reaction mixture was poured onto saturated NH₄Cl solution and wasextracted with EtOAc. The combined organic layers were dried over Na₂SO₄and were concentrated in vacuo.

The residue was purified by chromatography (silica gel, 20 g, 0% to 50%EtOAc in heptane) to obtain the title compound (1.33 g, 69%) as a whitesolid. MS (ESI): m/z=331.13 [M−H]⁻.

Step 4: 2-tert-Butyl-5-methyl-4-methylsulfonyl-phenol

To a solution of1-benzyloxy-2-tert-butyl-5-methyl-4-methylsulfonyl-benzene (1.2 g) in amixture of MeOH (100 mL) and EtOAc (100 mL) was added Pd(C) (10% oncharcoal, 200 mg) under an atmosphere of argon. The reaction vessel wasthen evacuated and purged with hydrogen and the reaction mixture wasstirred for 18 h. The reaction mixture was filtered over dicalite andthe filtrate was concentrated in vacuo to give the title compound (865mg, 99%) as a white solid. MS (ESI): m/z=241.09 [M−H]⁻.

Intermediate D26-B:

3-Bromomethyl-1-(4-methoxy-benzyl)-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine

Step 1: 4-Hydrazino-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethylester

To a solution of hydrazine hydrate (6.28 mL) in ethanol (100 mL) wasadded drop wise a solution of4-chloro-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (10g, CAS: 5909-24-0) in ethanol (250 mL) at 0° C. and the reaction mixturewas stirred at 25° C. for 1 h. All volatiles were removed under reducedpressure to afford the title compound (12.0 g) as an off white solidwhich was used in the next reaction step without additionalpurification. MS (ESI): m/z=229.5 [M+H]⁺.

Step 2: 6-Methylsulfanyl-1,2-dihydro-pyrazolo[3,4-d]pyrimidin-3-one

A solution of 4-hydrazino-2-methylsulfanyl-pyrimidine-5-carboxylic acidethyl ester (12.0 g) in 10% aqueous KOH solution (300 mL) was refluxedfor 15 min. The reaction mixture was then cooled to 0° C. and wasacidified with 25% aq. AcOH. The resulting precipitate was filtered off,dried under reduced pressure and co-evaporated with toluene to affordthe title compound (6.3 g, 66%) as off white solid. MS (ESI): m/z=183.2[M+H]⁺.

Step 3: 3-Bromo-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine

A mixture of 6-methylsulfanyl-1,2-dihydro-pyrazolo[3,4-d]pyrimidin-3-one(4.5 g) and POBr₃ (21.21 g) was heated in a sealed tube to 170° C. for 8h. The reaction mixture was cooled to 25° C., diluted with water andbasified with 25% aq. ammonia solution and was then extracted withEtOAc. The combined organic layers were washed with brine, dried overNa₂SO₄, filtered and evaporated under reduced pressure to afford thetitle compound (2.41 g, 40%) as a light brown solid. MS (ESI): m/z=245.1[M+H]⁺.

Step 4:3-Bromo-1-(4-methoxy-benzyl)-6-methylsulfanyl-1I-pyrazolo[3,4-d]pyrimidine

To a solution of 3-bromo-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine(3.6 g) in anhydrous DMF (100 mL) was added Cs₂CO₃ (7.16 g) at 25° C.and the reaction mixture was stirred at 25° C. for 15 min. Then,1-(chloromethyl)-4-methoxy-benzene (2.39 mL) was added dropwise at 25°C. and the reaction mixture was stirred at 25° C. for 16 h. The reactionmixture was filtered and the filtrate was diluted with water andextracted with EtOAc. The combined organic extracts were dried overNa₂SO₄, filtered and evaporated under reduced pressure. The residue waspurified by column chromatography over silica gel (3-6% EtOAc in hexane)to afford the title compound (4 g, 75%) as an off white solid. MS (ESI):m/z=367.1 [M+H]⁺.

Step 5:1-(4-Methoxy-benzyl)-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid methyl ester

To a solution of3-bromo-1-(4-methoxy-benzyl)-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine(2.0 g) in a mixture of anhydrous DMF (30 mL) and MeOH (25 mL) wereadded Pd(OAc)₂ (98 mg), DPPP (135 mg) followed by Et₃N (2.34 mL) at 25°C. The reaction mixture was stirred under an atmosphere of carbonmonoxide at 70 PSI and at 70° C. for 16 h. The reaction mixture wasfiltered through celite and the solvent was evaporated under reducedpressure. The residue was purified by column chromatography over silicagel (15-20% EtOAc in hexane) to afford the title compound (1.38 g, 73%)as off white solid. MS (ESI): m/z=345.3 [M+H]⁺.

Step 6:[1-(4-Methoxy-benzyl)-6-methylsulfanyl-4,7-dihydro-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-methanol

A suspension of NaBH₄ (2.64 g) and CaCl₂) (3.87 g) in a mixture of THF(90 mL) and EtOH (90 mL) was cooled to 0° C. and a solution of-(4-methoxy-benzyl)-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid methyl ester (3.0 g) in anhydrous THF (60 mL) was added drop wise.The reaction mixture was stirred at 0° C. for 2 h and was then quenchedby slow addition of water at 0° C., followed by dilution with EtOAc. Theorganic layer was separated and the aqueous layer was extracted withEtOAc. The combined organic layers were washed with brine, dried overNa₂SO₄, filtered and evaporated to afford the title compound (2.67 g,97%) as an off white solid. MS (ESI): m/z=319.2 [M+H]⁺.

Step 7:[1-(4-Methoxy-benzyl)-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-methanol

A suspension of[1-(4-methoxy-benzyl)-6-methylsulfanyl-4,7-dihydro-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-methanol(2.67 g) and chloranil (2.064 g) in anhydrous toluene (100 mL) wasrefluxed for 2 h. The reaction mixture was cooled to 25° C. and EtOAcand water were added. The organic layer was separated, washed withbrine, dried over Na₂SO₄ and evaporated under reduced pressure. Theresulting residue was purified by column chromatography over silica gel(50-70% EtOAc in hexane) to afford the title compound (2.2 g, 83%) as anoff white solid. MS (ESI): m/z=317.0 [M+H]⁺.

Step 8:3-Bromomethyl-1-(4-methoxy-benzyl)-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine

To a solution of[1-(4-methoxy-benzyl)-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-methanol(1.5 g) in anhydrous acetonitrile (100 mL) was added PBr₃ (0.586 mL)dropwise at 25° C. and the reaction mixture was stirred at 25° C. for 2h. The mixture was diluted with EtOAc and washed with saturated aqueousNaHCO₃ solution and brine. The organic layer was dried over Na₂SO₄,filtered and evaporated under reduced pressure. The resulting residuewas purified by column chromatography over silica gel (10-14% EtOAc inhexane) to afford the title compound (1.26 g, 70%) as an off whitesolid. MS (ESI): m/z=381.0 [M+H]⁺.

Intermediate D3-A:

tert-Butyl3-[(2-tert-butyl-4-chloro-5-methyl-phenoxy)methyl]pyrazolo[3,4-b]pyridine-1-carboxylate

A suspension of 2-tert-butyl-4-chloro-5-methyl-phenol (61.0 mg. CAS:30894-16-7), tert-butyl3-(bromomethyl)pyrazolo[3,4-b]pyridine-1-carboxylate (95.8 mg, CAS:174180-76-8, prepared according to WO200876223A1) and potassiumcarbonate (106 mg) in acetone (2.5 mL) was heated to 50° C. for 3 h.Acetone was removed in vacuo and the residue was diluted with saturatedNH₄Cl solution. The mixture was extracted with EtOAc and the combinedorganic layers were washed with brine, dried over Na₂SO₄ and evaporated.The residue was purified by chromatography (20 g silica gel;heptane/EtOAc 90:10-75:25) to obtain the title compound as white solid(89 mg, 67%). MS (ESI): m/z=428.4 [M−H]⁻.

The following intermediates were synthesized from suitable buildingblocks in analogy to Intermediate D3-A:

Inter. Systematic Name Building blocks MS, m/z D4-A tert-Butyl3-[(2-tert-butyl-4-cyano-5- methyl- phenoxy)methyl]pyrazolo[3,4-b]pyridine-1-carboxylate

tert-butyl 3- (bromomethyl)pyrazolo[3,4- b]pyridine-1-carboxylate (CAS:174180-76-8) and Intermediate A16 321.2 [M − CO₂tBu + H]⁺ D5-Atert-Butyl 3-[(4-chloro-2-isoxazol-5- yl-5-methyl-phenoxy)methyl]pyrazolo[3,4- b]pyridine-1-carboxylate

tert-butyl 3- (bromomethyl)pyrazolo[3,4- b]pyridine-1-carboxylate (CAS:174180-76-8) and 4-chloro-2-(5-isoxazolyl)-5- methylphenol (CAS:213690-32-5) 441.3 [M + H]⁺ D6-A tert-Butyl 3-[(2-tert-butyl-4-chloro-5-methyl-phenoxy)methyl]-6-fluoro- pyrazolo[3,4-b]pyridine-1-carboxylate

tert-butyl 3-(bromomethyl)-6- fluoro-pyrazolo[3-4-b]pyridine-1-carboxylate (CAS: 920036-30-2, prepared according to J. Med. Chem.2008, 51, 6503-6511) and 2-tert-butyl-4-chloro-5-methyl- phenol (CAS:30894-16-7) 348.2 [M − CO₂tBu + H]⁺ D9-A tert-Butyl3-[(2-tert-butyl-5-methyl- 4-methylsulfonyl-phenoxy)methyl]pyrazolo[3,4- b]pyridine-1-carboxylate

tert-butyl 3- (bromomethyl)pyrazolo[3,4- b]pyridine-1-carboxylate (CAS:174180-76-8) and Intermediate D9 474.3 [M + H]⁺ D10-A tert-Butyl3-[(2-tert-butyl-5-methyl- 4-methylsulfonyl- phenoxy)methyl]indazole-1-carboxylate

tert-butyl 3-(bromomethyl)- 1H-indazole-1-carboxylate (CAS 174180-42-8)and Intermediate D9 373.2 [M − CO₂tBu + H]⁺ D12-A tert-Butyl3-[(2-tert-butyl-4-chloro- 5-fluoro-phenoxy)methyl]-6-fluoro-pyrazolo[3,4-b]pyridine-1- carboxylate

tert-butyl 3-(bromomethyl)-6- fluoro-pyrazolo[3,4-b]pyridine-1-carboxylate (CAS: 920036-30-2) and Intermediate A2 450.2 [M − H]⁻D16-A tert-Butyl 3-[[4-chloro-2-[3-(2- methoxyethylcarbamoyl)phenyl]-5-methyl- phenoxy]methyl]pyrazolo[3,4- b]pyridine-1-carboxylate

tert-butyl 3- (bromomethyl)pyrazolo[3,4- b]pyridine-1-carboxylate (CAS:174180-76-8) and Intermediate B17 451.2 [M + H]⁺ D18-A tert-Butyl3-[[4-chloro-2-[3- (dimethylcarbamoyl)phenyl]-5- methyl-phenoxy]methyl]pyrazolo[3,4- b]pyridine-1-carboxylate

tert-butyl 3- (bromomethyl)pyrazolo[3,4- blpyridine-1-carboxylate (CAS:174180-76-8) and Intermediate B12 421.2 [M + H]⁺ D39-A tert-Butyl3-[[4-chloro-2-[2-fluoro-5- (4-methyl-3-oxo-piperazine-1-carbonyl)phenyl]-5-methyl- phenoxy]methyl]pyrazolo[3,4-b]pyridine-1-carboxylate

tert-butyl 3- (bromomethyl)pyrazolo[3,4- b]pyridine-1-carboxylate (CAS:174180-76-8) and Intermediate B65 508.2 [M − CO₂tBu + H]⁺ D40-Atert-Butyl 3-[[4-chloro-2-[2-fluoro-5-[2-methoxyethyl(methyl)carbamoyl]- phenyl]-5-methyl-phenoxy]methyl]pyrazolo[3,4- b]pyridine-1-carboxylate

tert-butyl 3- (bromomethyl)pyrazolo[3,4- b]pyridine-1-carboxylate (CAS:174180-76-8) and Intermediate B73 584.3 [M + H]⁺ D41-A tert-Butyl3-[[4-chloro-2-[2-fluoro-5-[ (4-methyl-3-oxo-piperazine-1-carbonyl)phenyl]-5-methyl- phenoxy]methyl]indazole-1- carboxylate

tert-butyl 3-(bromomethyl)- 1H-indazole-1-carboxylate (CAS 174180-42-8)and Intermediate B65 507.2 [M − CO₂tBu +H]⁺ D42-A tert-Butyl3-[[4-chloro-2-[2-fluoro-5- (pyrrolidine-1-carbonyl)phenyl]-5- methyl-phenoxy]methy]pyrazolo[3,4- b]pyridine-1-carboxylate

tert-butyl 3- (bromomethyl)pyrazolo[3,4- b]pyridine-1-carboxylate (CAS:174180-76-8) and Intermediate B62 565.2 [M + H]⁺ D43-A tert-Butyl3-[[5-chloro-4-cyano-2-[2- fluoro-5-(pyrrolidine-1-carbonyl)phenyl]phenoxy]methyl] pyrazolo[3,4-b]pyridine-1- carboxylate

tert-butyl 3- (bromomethyl)pyrazolo[3,4- b]pyridine-1-carboxylate (CAS:174180-76-8) and Intermediate D43 576.18 [M + H]⁺ D45-A tert-Butyl3-[(2-tert-butyl-4- methylsulfonyl- phenoxy)methyl]pyrazolo[3,4-b]pyridine-1-carboxylate

tert-butyl 3- (bromomethyl)pyrazolo[3,4- b]pyridine-1-carboxylate (CAS:174180-76-8) and Intermediate A15 360.1 [M − CO₂tBu + H]⁺Intermediate D43:

2-Chloro-5-[2-fluoro-5-(pyrrolidine-1-carbonyl)phenyl]-4-hydroxy-benzonitrile

Step 1:2-Chloro-5-[2-fluoro-5-(pyrrolidine-1-carbonyl)phenyl]-4-(methoxymethoxy)benzonitrile

The title compound was prepared in analogy to Intermediate B31, step 3,from 5-bromo-2-chloro-4-methoxymethoxy-benzonitrile (Intermediate B31,step 2) (80 mg) and (2-fluoro-5-(pyrrolidine-1-carbonyl)phenyl)boronicacid (82.3 mg, CAS: 874289-42-6) and was obtained as a white foam (60mg, 52%). MS (ESI): m/z=389.2 [M+H]⁺.

Step 2:2-Chloro-5-[2-fluoro-5-(pyrrolidine-1-carbonyl)phenyl]-4-hydroxy-benzonitrile

To a suspension of4-chloro-2′-fluoro-6-(methoxymethoxy)-5′-(pyrrolidine-1-carbonyl)-[1,1′-biphenyl]-3-carbonitrile(50 mg) in dioxane (3 mL) was added 4M HCl in dioxane (257 μL) dropwiseover a period of 2 minutes at rt. The resulting solution was stirred atrt for 2 h. Then again, 4M HCl in dioxane (129 μL) was added andstirring was continued for 5 h. The reaction mixture was evaporated todryness and the residue was purified by recrystallization from DCM andheptane to afford the title compound (40 mg, 88%) as a white solid. MS(ESI): m/z=386.2 [M+CH₃CN+H]⁺.

Intermediate D44-B:

3-(Chloromethyl)-1-tritylpyrazolo[3,4-c]pyridine

Step 1: Ethyl 1-tritylpyrazolo[3,4-c]pyridine-3-carboxylate

In a 20 mL round-bottomed flask, ethyl1H-pyrazolo[3,4-c]pyridine-3-carboxylate (CAS: 1053656-33-9, 500 mg) wascombined with DMF (3 mL). Triethylamine (397 mg) was added to give alight brown solution. The mixture was cooled at 0° C. and then[chloro(diphenyl)methyl]-benzene (802 mg) was slowly added. The reactionmixture was stirred for 4 h. The reaction mixture was poured into 20 mLethyl acetate and the organic solution was washed with H₂O (2×10 mL).The aqueous washings were re-extracted with ethyl acetate. The organiclayers were combined, dried over Na₂SO₄ and concentrated in vacuo.Residual DMF was removed by addition of toluene followed by evaporationin vacuo. The crude material was purified by flash chromatography(silica gel, 20 g, gradient of 0% to 60% ethyl acetate in heptane) togive the title compound as a colorless foam (700 mg). MS (m/z): 434.18[M+H]⁺.

Step 2: (1-Tritylpyrazolo[3,4-c]pyridin-3-yl)methanol

In a 20 mL round-bottomed flask, ethyl1-trityl-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (700 mg) was combinedwith CH₂Cl₂ (3 mL) and was then cooled to −78° C. Diisobutylalumniumhydride solution (1 M in CH₂CL₂, 3.2 mL) was added slowly and themixture was allowed to stir at −78° C. for 2 h. The reaction mixture waspoured into 20 mL ethyl acetate and Rochelle salt solution (10 mL) andwas extracted with ethyl acetate (2×10 mL). The organic layers werecombined, dried over Na₂SO₄ and concentrated in vacuo to give a whitefoam (500 mg), that was used without further purification. MS (m/z):392.17 [M+H]⁺.

Step 3: 3-(Chloromethyl)-1-tritylpyrazolo[3,4-c]pyridine

In a 20 mL round-bottomed flask,(1-trityl-1H-pyrazolo[3,4-c]pyridin-3-yl)methanol (55 mg) was combinedwith CH₂Cl₂ (3 mL) and the mixture was cooled to 0° C. Thionyl chloride(20.4 μL) was then added dropwise. The ice bath was removed and thereaction was allowed to stir at rt for 1 hr. The mixture was quenchedwith aq. sodium bicarbonate solution and the organic layer wasseparated, washed with brine and dried over Na₂SO₄. The solution wasconcentrated in vacuo to provide the title compound as a colorless foam(53 mg). MS (m/z): 410.14 [M+H]⁺.

Intermediate D54-B

3-(Chloromethyl)-1-tritylpyrazolo[4,3-c]pyridine

Step 1: Ethyl 1H-pyrazolo[4,3-c]pyridine-3-carboxylate

Under an argon atmosphere, thionyl chloride (241 mg, 147 μl) was addedto a solution of 1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (300 mg,CAS: 932702-11-9) in ethanol (20 mL). The mixture was then heated toreflux and was allowed to stir for 2 hours. The mixture was cooled toroom temperature and was quenched with sat. Na₂CO₃ solution. The aqueouslayer was extracted twice with ethyl acetate (80 mL). The organic layerswere washed once with brine, dried over Na₂SO₄, filtered, evaporated anddried at high vacuum to provide the title compound as a light yellowpowder (228 mg, 62%). MS (m/z): 192.1 [M+H]⁺.

Steps 2-4: 3-(Chloromethyl)-1-tritylpyrazolo[4,3-c]pyridine

This material was obtained as a solid in exact analogy to IntermediateD44-B, Steps 1-3, from ethyl 1H-pyrazolo[4,3-c]pyridine-3-carboxylate(obtained above in Step 1) first by tritylation, then reduction to thehydroxymethyl derivative, and finally chlorination. MS (m/z): 410.2[M+H]⁺.

Intermediates F

Intermediate F1:

tert-Butyl 3-(bromomethyl)pyrazole-1-carboxylate

Step 1: tert-Butyl 3-methylpyrazole-1-carboxylate

To a solution of 3-methyl-1H-pyrazole (500 mg) in acetonitrile (10 mL)were added di-tert-butyl dicarbonate (1.59 g, 1.7 mL) and DMAP (74.4 mg)at 0° C. The mixture was allowed to warm to rt and was stirred for 2 h.Then, EtOAc was added and the mixture was washed with 0.1 N HCl,saturated NaHCO₃ solution and brine, dried with Na₂SO₄ and evaporated.The crude product (containing ˜15% of tert-butyl5-methylpyrazole-1-carboxylate) was used in the next reaction stepwithout further purification.

Step 2: tert-Butyl 3-(bromomethyl)pyrazole-1-carboxylate

A mixture of tert-butyl 3-methylpyrazole-1-carboxylate (1.24 g), NBS(1.7 g) and benzoyl peroxide (308 mg) in CCl₄ (50 mL) was heated toreflux for 4 h. The mixture was then cooled to 0° C., filtered andevaporated. The residue was purified by column chromatography (10 gSiO₂, n-heptane/EtOAc 100/0 to 90/10) to provide the title compound (481mg, 27%) as a colorless oil. MS (ESI): m/z=161.0 [M-CO₂tBu+H]⁺.

Intermediate F3:

Methyl 5-(hydroxymethyl)-2-tetrahydropyran-2-yl-pyrazole-3-carboxylate

Step 1: Dimethyl 1-tetrahydropyran-2-ylpyrazole-3,5-dicarboxylate

TFA (74.0 mg, 50 μL) was added to a suspension of dimethyl1H-pyrazole-3,5-dicarboxylate (1.546 g, CAS: 4077-76-3) in toluene (15mL) and the mixture was heated to 80° C. Then, 3,4-dihydro-2H-pyran (828mg, 900 μL) was added and the reaction mixture was refluxed overnight.The mixture was cooled to rt and the solvent was evaporated. The residuewas dissolved in water and was extracted with EtOAc. The combinedorganic layers were washed with brine, dried with Na₂SO₄, filtered andevaporated. The residue was purified by chromatography (50 g silica gel;heptane/EtOAc 100/0 to 50/50) to obtain the title compound (1.95 g, 87%)as a white solid. MS (ESI): m/z=185.1 [M-THP+H]⁺.

Step 2: Methyl5-(hydroxymethyl)-2-tetrahydropyran-2-yl-pyrazole-3-carboxylate

To a solution of dimethyl1-tetrahydropyran-2-ylpyrazole-3,5-dicarboxylate (1.95 g) in a mixtureof THF (40 mL) and diethyl ether (80 mL) was added a 1M solution ofDIBAL-H in toluene (16.0 mL) dropwise at −78° C. and the mixture wasstirred for 3 h at −78° C. Then, more DIBAL-H 1 M in toluene (8 mL) wasadded and the mixture was stirred for another hour. The mixture waswarmed to 0° C. and water (15 mL) was added dropwise. The whitesuspension was evaporated and the remaining white cake was suspended inMeOH (120 mL), flushed with CO₂ (g) for 10 minutes and then refluxed for5.5 h. The mixture was filtered and the filtrate was concentrated. Theremaining material was purified by chromatography (50 g silica gel,heptane/EtOAc 100/0 to 1/2) to obtain the title compound (810 mg, 47%)as a white solid. MS (ESI): m/z=157.0 [M-THP+H]⁺.

Examples A: Triazolones with R_(A)≠Aryl Example A13-[(2-tert-Butyl-4-chloro-5-methylphenoxy)methyl]-4-methyl-1H-1,2,4-triazol-5-one

2-(tert-Butyl)-4-chloro-5-methylphenol (CAS: 30894-16-7, 250 mg),3-(chloromethyl)-4-methyl-1H-1,2,4-triazol-5(4H)-one (CAS: 1338226-21-3;279 mg), potassium carbonate (348 mg) and potassium iodide (20.9 mg)were combined in acetone (10.0 mL) at rt under an argon atmosphere. Themixture was then heated to reflux for 3 hours and was then kept at rtfor another 16 hours. TLC showed no residual starting material at thattime. The reaction mixture was then poured into ice/water and theaqueous layer was extracted twice with ethyl acetate. The organic layerswere washed once with brine, dried over Na₂SO₄, filtered and evaporated.The crude material was purified by flash chromatography on silica gelwith 0% to 70% ethyl acetate in heptane as an eluent to provide thetitle compound as a colorless solid (60 mg). MS (m/z): 310.2 [MH]⁺.

The following examples were synthesized from the suitable buildingblocks/intermediates and known3-(chloromethyl)-4-methyl-1H-1,2,4-triazol-5(4H)-one in analogy toExample A1:

Building block/ Ex. Systematic Name intermediate MS, m/z A2

Intermediate A1 314.2 [M + H]⁺ A3

6-Isopropyl-3,3-dimethyl-2,3- dihydro-1H-inden-5-ol CAS: 1588508-77-3made according to WO2014048865 316.2 [M + H]⁺ A4

2-tert-butyl-4-(3-methyl- 1,2,4-oxadiazol-5-yl)phenol Intermediate A4344.2 [M + H]⁺ A5

2-tert-butyl-4-[1-(2- trimethylsilylethoxymethyl)- imidazol-2-yl]phenolIntermediate A5 457.9 [M + H]⁺ A6

2-tert-butyl-4-(1- methylimidazol-2-yl)phenol Intermediate A6 342.0 [M +H]⁺ A7

2-tert-butyl-4-(1,3-oxazol-2- yl)phenol Intermediate A7 329.0 [M + H]⁺A8

2-tert-butyl-4-morpholin-4- ylphenol Intermediate A8 347.0 [M + H]⁺ A9

2-tert-butyl-4-(3- methylimidazol-4-yl)phenol Intermediate A9 342.0 [M +H]⁺ A10

2-tert-butyl-4-(5-methyl- 1,3,4-oxadiazol-2-yl)phenol Intermediate A10344.1 [M + H]⁺ A11

4-hydroxy-3-propan-2- ylbenzonitrile CAS: 46057-54-9 Made from2-isopropylphenol according to WO2005023762 271.12 [M − H]⁻ A12

4-hydroxy-6-methyl-3- propan-2-ylbenzonitrile CAS: 858026-56-9 Made from2-isopropyl-5- methlyphenol according to WO2005023762 285.14 [M − H]⁻A13

3-tert-butyl-4- hydroxybenzonitrile CAS: 4910-04-7 287.15 [M + H]⁺ A14

4-chloro-2-cyclopropyl-5- methylsulfonylphenol Intermediate A14 358.06[M + H]⁺ and 375.09 [M + NH₄]⁺ A15

2-tert-butyl-4- methylsulfonylphenol Intermediate A15 340.13 [M + H]⁺A16

5-tert-butyl-4-hydroxy-2- methylbenzonitrile Intermediate A16 301.17[M + H]⁺ A17

4-tert-butyl-5-hydroxy-2- methylbenzonitrile Intermediate A17 301.17[M + H]⁺. A18

2-tert-Butyl-4-[3-(2- trimethylsilanyl- ethoxymethyl)-3H-imidazol-4-yl]-phenol Intermediate A18 458.10 [M + H]⁺ A19

4-chloro-2-cyclopropyl-5- methylphenol Intermediate A19 294.0 [M + H]⁺A20

4-chloro-2-cyclohexyl-5- methylphenol Intermediate A20 336.0 [M + H]⁺A21

4-chloro-5-methyl-2-(oxan-4- yl)phenol Intermediate A21 338.0 [M + H]⁺A22

2-chloro-4-cyclopropyl-5- hydroxy-benzonitrile Intermediate A22 305.0[M + H]⁺ A23

N-(2-chloro-4-cyclopropyl-5- hydroxyphenyl)methane- sulfonamideIntermediate A23 373.0 [M + H]⁺ A24

4-tert-butyl-3- hydroxybenzonitrile Intermediate A24 287.0 [M + H]⁺ A25

4-tert-butyl-3- hydroxybenzamide Intermediate A25 305.6 [M + H]⁺

Example A265-tert-Butyl-2-methyl-4-[(5-oxo-4-propan-2-yl-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile

Step 1: 3-(Benzyloxymethyl)-4-isopropyl-1H-1,2,4-triazol-5(4H)-one

To a suspension of N-isopropylhydrazinecarboxamide hydrochloride (CAS:35578-82-6, 1.0 g) in THF (12.5 mL) was added 2-(benzyloxy)acetylchloride (1.2 g) and the mixture was cooled to 0° C. To the mixture wasthen added dropwise 5M aq. sodium hydroxide (2.67 mL) over 3 minutes andthe reaction mixture was vigorously stirred at room temperature for 2.5hours. THF was then removed by evaporation in vacuo. The remainingbrown, viscous suspension was treated with 2M aq. sodium hydroxide (6.51mL) and was heated to 95° C. (oil bath temperature) for 16 hours. Aftercooling, the turbid solution was adjusted to pH 4 using 25% aq. HC.Ethyl acetate was added and the layers were separated. The aqueous layerwas extracted twice with ethyl acetate. The organic layers were washedwith brine, dried over MgSO₄, filtered, treated with silica gel andevaporated. The residue was purified by silica gel chromatography with agradient of n-heptane in ethyl acetate (100/0 to 0/100) to provide thetitle compound (0.705 g). MS (m/z): 248.14 [M+H]⁺

Step 2: 3-(Hydroxymethyl)-4-propan-2-yl-1H-1,2,4-triazol-5-one

To a solution of3-(benzyloxymethyl)-4-isopropyl-1H-1,2,4-triazol-5(4H)-one (0.70 g) inethanol (12 mL) under argon was added palladium hydroxide on carbon(20%, 298 mg) and the reaction mixture was stirred under a hydrogenatmosphere at room temperature and 0.5 bar overpressure over 18 hours.The reaction mixture was then filtered and the solid was washed withethanol (10 mL). The filtrate was evaporated to provide the titlecompound as a colorless solid (0.391 g). MS (m/z): 157.0 [M]⁺.

Step 3: 3-(Chloromethyl)-4-propan-2-yl-1H-1,2,4-triazol-5-one

To a suspension of3-(hydroxymethyl)-4-isopropyl-1H-1,2,4-triazol-5(4H)-one (0.30 g) inacetonitrile (6 mL) was added thionyl chloride (261 mg) and thesuspension rapidly turned into a solution. The mixture was stirred atroom temperature for 16 hours. The reaction mixture was evaporated andthe residue was twice treated with toluene and evaporated again toremove the remaining thionyl chloride. The residue, an off-white solid,was triturated with n-heptane in an ultrasonic bath. The suspension wasthen filtered, washed with n-heptane and the solid was dried in vacuo toprovide the title compound (0.37 g) as a colorless solid. MS (m/z):175.0 [M]⁺.

Step 4:5-tert-Butyl-2-methyl-4-[(5-oxo-4-propan-2-yl-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile

This material was obtained from in analogy to Example 1 from3-(chloromethyl)-4-propan-2-yl-1H-1,2,4-triazol-5-one and5-tert-butyl-4-hydroxy-2-methylbenzonitrile (Intermediate A16) toprovide the title compound as a light brown solid. MS (m/z): 329.20[M+H]⁺.

Example A274-Methyl-3-[(5-methyl-2-propan-2-ylphenoxy)methyl]-1H-1,2,4-triazol-5-one

Step 1:4-Methyl-3-[(5-methyl-2-propan-2-ylphenoxy)methyl]-5-methylsulfonyl-1,2,4-triazole

To a solution of 2-isopropyl-5-methylphenol (300 mg, CAS: 89-83-8) inacetone (20 mL) was added K₂CO₃ (387 mg) and3-(iodomethyl)-4-methyl-5-(methylsulfonyl)-4H-1,2,4-triazole (783 mg,CAS: 1068603-49-5, made according to WO2008119662). The reaction mixturewas stirred over night at 60° C. and was then extracted with water (150mL) and EtOAc (150 mL). The organic layer was washed with water (150mL), dried over Na₂SO₄, filtered and evaporated. The crude material waspurified by column chromatography (gradient of up to 50% EtOAc in DCM)to provide the title compound as a yellow gum (0.241 g). MS (m/z):324.14 [M+H]⁺.

Step 2:3-Methoxy-4-methyl-5-[(5-methyl-2-propan-2-ylphenoxy)methyl]-1,2,4-triazole

To a suspension of4-methyl-3-[(5-methyl-2-propan-2-ylphenoxy)methyl]-5-methylsulfonyl-1,2,4-triazole(241 mg) in methanol (8 mL) was added sodium methoxide in methanol (0.6mL, 5.4 M). The reaction mixture was heated at 85° C. under reflux.After 2 h, the reaction was stopped and cooled. The mixture was dilutedwith EtOAc (50 mL), washed with sat. aqueous NaHCO₃ (50 mL) and sat.NaCl solution (20 mL) and was then dried over Na₂SO₄ and concentrated invacuo. The desired product was obtained as such as a light yellow solidand was used without further purification (0.2 g, containing somestarting material). MS (m/z): 276.17 [M+H]⁺.

Step 3:4-Methyl-3-[(5-methyl-2-propan-2-ylphenoxy)methyl]-1H-1,2,4-triazol-5-one

To a solution of3-methoxy-4-methyl-5-[(5-methyl-2-propan-2-ylphenoxy)methyl]-1,2,4-triazole(113 mg) in AcOH (29 mL) was added HBr (19.5 mL of a 48% solution) at rtand the reaction mixture was stirred over night. The solution wasconcentrated (at 50-70° C. water bath temperature) and was then dilutedwith DCM (50 mL) and washed with 2M KHCO₃ solution (30 mL). The organiclayer was dried with Na₂SO₄, filtered and concentrated to give the titlecompound as a light yellow solid (0.094 g). MS (m/z): 262.2 [M+H]⁺.

The following Examples were synthesized from the suitable buildingblocks/intermediates in analogy to Example A1 Steps 1-3:

Building block/ Ex. Systematic Name intermediate MS, m/z A28

4-chloro-5-methyl-2-propan- 2-ylphenol CAS: 89-68-9 296.12 [M + H]⁺ A29

4-chloro-2-propan-2-ylphenol CAS: 54461-05-1 282.10 [M + H]⁺ A30

6-cyclopropyl-2- methylbenzo[d]thiazol-5-ol Intermediate A30 317.11 [M +H]⁺ A31

4-chloro-2-cyclobutyl-5- methylphenol Intermediate A31 308.2 [M + H]⁺

Example A323-[[2-tert-butyl-4-(1H-imidazol-2-yl)phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one

To a solution of3-[[2-tert-butyl-4-[1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one(45 mg), obtained in Example A5, in anhydrous THF (10 mL) at 0° C. wasadded 2N aqueous HCl (3 mL) at 0° C. and the reaction mixture wasstirred at 25° C. for 8 h. The solvent was evaporated under reducedpressure and the residue was diluted with water, basified usingsaturated aq. NaHCO₃ solution and extracted with DCM (2×30 mL). Thecombined organic layers were washed with brine, dried over Na₂SO₄ andevaporated under reduced pressure. The residue was purified columnchromatography over silica gel (gradient of 3-5% MeOH in DCM) to affordthe title compound (12 mg) as an off white solid. MS (m/z): 328.1[M+H]⁺.

The following Example was synthesized from the suitable buildingblocks/intermediates in analogy to Example A32, with the exception thatthe solvent THF was replaced by DCM and that 2N HCl was replaced bytrifluoroacetic acid.

Building Ex. Systematic Name block/intermediate MS, m/z A33

Example A18 328.20 [M + H]⁺

Example A344-tert-Butyl-2-chloro-5-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile

This material was made in analogy to Example A1 from Intermediate A34and commercial 3-(chlormethyl)-4-methyl-1H-1,2,4-triazol-5(4H)-one (CAS:1338226-21-3) as a colorless solid. MS (m/z): 321.2 [M+H]⁺.

Example A355-tert-butyl-2-chloro-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile

To 5-tert-butyl-2-chloro-4-hydroxy-benzonitrile (2.29 g, 10.9 mmol) inN-methyl-pyrrolidinone (55 mL) was added NaH (568 mg, 14.2 mmol). Themixture was stirred at room temperature for 30 min.3-(Chloromethyl)-4-methyl-1H-1,2,4-triazol-5(4H)-one (1.93 g, 13.11mmol) was dissolved in N-methyl-pyrrolidinone (20 mL) and added dropwisevia addition funnel over 30 min. Upon complete addition, water (160 mL)was slowly added to the reaction. After stirring until cooled to roomtemperature, the reaction was filtered and solids dried to give 3.15 gof the title compound as a white solid (90% yield). MS (m/z): 321.5[M+H]⁺.

Example A365-tert-butyl-2-fluoro-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile

The title compound was prepared in analogy to example A35, from5-tert-butyl-2-fluoro-4-hydroxy-benzonitrile (0.118 g) and3-(chloromethyl)-4-methyl-1H-1,2,4-triazol-5(4H)-one (0.108 g) and wasobtained (17 mg, 9%) as a white solid. MS (m/z): 305.5 [M+H]⁺.

Examples B: Triazolones with R_(A)=Aryl and Heteroaryl Example B13-[(4-Chloro-5-methyl-2-phenylphenoxy)methyl]-4-methyl-1H-1,2,4-triazol-5-one

To a solution of 4-chloro-5-methyl-2-phenylphenol (62.2 mg, IntermediateB1) in acetone (2 mL) was added K₂CO₃ (42.6 mg) and3-(chloromethyl)-4-methyl-1H-1,2,4-triazol-5(4H)-one (35 mg, CAS:1338226-21-3). The reaction mixture was stirred for 2 hours at reflux.The reaction mixture was poured on 10% aqueous NH₄Cl solution (30 mL)and EtOAc (30 mL) and the layers were separated. The aqueous layer wasextracted a second time with EtOAc (30 mL). The organic layers werewashed with brine (30 mL), dried over MgSO₄, filtered and concentratedin vacuo. The residue was purified by silica gel chromatography on a 20g column using an Flashmaster MPLC-system eluting with a gradient ofDCM:MeOH (100/0 to 50/50) to give the title compound as an off-whitesolid (7 mg, 9%). MS (ESI): m/z=330.100 [M+H]⁺.

The following Examples were synthesized from the suitable buildingblocks/intermediates and known3-(chloromethyl)-4-methyl-1H-1,2,4-triazol-5(4H)-one in analogy toExample B1:

Building block/ Ex. Systematic Name intermediate MS, m/z B2

4-chloro-2-(2-chlorophenyl)- 5-methylphenol Intermediate B2 364.06 [M +H]⁺ B3

4-chloro-2-(3-chlorophenyl)- 5-methylphenol Intermediate B3 364.06 [M +H]⁺ B4

4-chloro-2-(4-chlorophenyl)- 5-methylphenol Intermediate B4 364.06 [M +H]⁺ B5

3-(5-chloro-2-hydroxy-4- methylphenyl)benzonitrile Intermediate B5355.10 [M + H]⁺ B6

4-chloro-5-methyl-2-(3- methylsulfonylphenyl)phenol Intermediate B6408.08 [M + H]⁺ B7

4-chloro-5-methyl-2-(2- methylsulfonylphenyl)phenol Intermediate B7408.08 [M + H]⁺ B8

[3-(5-chloro-2-hydroxy-4- methylphenyl)phenyl]- piperidin-1-ylmethanoneIntermediate B8 441.17 [M + H]⁺ B9

3-(5-chloro-2-hydroxy-4- methylphenyl)-N- cyclohexylbenzamideIntermediate B9 455.19 [M + H]⁺ B10

[3-(5-chloro-2-hydroxy-4- methylphenyl)phenyl]- morpholin-4-ylmethanoneIntermediate B10 443.15 [M + H]⁺ B11

3-(5-chloro-2-hydroxy-4- methylphenyl)benzamide Intermediate B11 373.11[M − H]⁻ B12

3-(5-chloro-2-hydroxy-4- methylphenyl)-N,N- dimethylbenzamideIntermediate B12 401.14 [M + H]⁺ B13

3-(5-chloro-2-hydroxy-4- methylphenyl)-N- phenylbenzamide IntermediateB13 449.14 [M + H]⁺ B14

3-chloro-5-(5-chloro-2- hydroxy-4- methylphenyl)benzamide IntermediateB14 407.07 [M + H]⁺ B15

3-(5-chloro-2-hydroxy-4- methylphenyl)-N- cyclopropyl-4- fluorobenzamideIntermediate B15 431.13 [M + H]⁺ B16

6-hydroxy-biphenyl-3- carbonitrile Intermediate B16 307.2 [M + H]⁺ B17

3-(5-chloro-2-hydroxy-4- methylphenyl)-N-(2- methoxyethyl)benzamideIntermediate B17 431.15 [M + H]⁺ B18

4-chloro-2-(2-chloropyridin- 3-yl)-5-methylphenol Intermediate B18365.06 [M + H]⁺ B19

4-chloro-2-(6-chloropyridin- 2-yl)-5-methylphenol Intermediate B19365.10 [M + H]⁺ B20

5-(5-chloro-2-hydroxy-4- methylphenyl)pyridine-3- carboxamideIntermediate B20 (Reaction carried out in DMF at 75° C. for 2.5 hours)374.01 [M + H]⁺ B21

4-chloro-2-(6- methoxypyridin-2-yl)-5- methylphenol Intermediate B21361.11 [M + H]⁺ B25

4-chloro-2-(5-isoxazolyl)-5- methylphenol CAS: 213690-32-5 321.08 [M +H]⁺ B26

4-chloro-5-methyl-2-oxazol- 5-yl-phenol Intermediate B26 321.0 [M + H]⁺B30

4-chloro-5-methyl-2-(2- methyl-2H-pyrazol-3-yl)- phenol Intermediate B30333.8 [M + H]⁺ B31

4-chloro-6-hydroxy-biphenyl- 3-carbonitrile Intermediate B31 341.1 [M +H]⁺ B32

4-chloro-4′-fluoro-6-hydroxy- biphenyl-3-carbonitrile Intermediate B32359.0 [M + H]⁺ B33

4′-chloro-5′-cyano-2′- hydroxy-biphenyl-3- carboxylic acid methylamideIntermediate B33 398.3 [M + H]⁺ B35

4-chloro-6-hydroxy-3′-(5- methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-3-carbonitrile Intermediate B35 423.1 [M + H]⁺ B36

3-(5-chloro-2-hydroxy-4- methyl-phenyl)-N-(2- hydroxyethyl)benzamideIntermediate B36 417.2 [M + H]⁺ B37

4-chloro-6-hydroxy-3′-(5- methyl-[1,3,4]oxadiazol-2-yl)-biphenyl-3-carbonitrile Intermediate B37 423.1 [M + H]⁺ B38

3-(5-chloro-2-hydroxy-4- methyl-phenyl)-4-fluoro-N,N- dimethyl-benzamideIntermediate B38 419.2 [M + H]⁺ B39

3-(4-chloro-5-cyano-2- hydroxy-phenyl)-N,N- dimethyl-benzamideIntermediate B39 412.1 [M + H]⁺ B40

[3-(5-chloro-2-hydroxy-4- methyl-phenyl)-4-fluoro- phenyl]-morpholino-methanone Intermediate B40 461.2 [M + H]⁺ B41

2-chloro-4-hydroxy-5-[3- (morpholine-4- carbonyl)phenyl]benzonitrileIntermediate B41 454.2 [M + H]⁺ B42

methyl 3-(5-chloro-2- hydroxy-4-methyl- phenyl)benzoate Intermediate B42388.1 [M + H]⁺ B44

methyl 3-[[3-(5-chloro-2- hydroxy-4-methyl- phenyl)benzoyl]amino]propan-oate Intermediate B44 459.2 [M + H]⁺ B46

ethyl 2-[[3-(5-chloro-2- hydroxy-4-methyl- phenyl)benzoyl]amino]acetateIntermediate B46 459.2 [M + H]⁺ B49

methyl 3-(5-chloro-2- hydroxy-4-methyl-phenyl)-4- methyl-benzoateIntermediate B49 402.1 [M + H]⁺ B52

3-(5-chloro-2-hydroxy-4- methyl-phenyl)-4- (trifluoromethoxy)benzamideIntermediate B52 457.2 [M + H]⁺ B53

4-chloro-2-(2-methoxy-3- pyridyl)-5-methyl-phenol Intermediate B53 361.1[M + H]⁺ B54

2-chloro-4-hydroxy-5-(2- methoxy-3- pyridyl)benzonitrile IntermediateB54 372.1 [M + H]⁺ B55

4-chloro-2-(5-ethoxy-2- fluorophenyl)-5-methylphenol Intermediate B55392.1 [M + H]⁺ B56

4-chloro-2-(2- methoxyphenyl)-5- methylphenol Intermediate B56 306.1[M + H]⁺ B57

4-chloro-2-(2-fluoro-5- propan-2-yloxyphenyl)-5- methylphenolIntermediate B57 406.2 [M + H]⁺ B58

4-chloro-2-[2-fluoro-5-(2- methylpropoxy)phenyl]-5- methylphenolIntermediate B58 420.2 [M + H]⁺ B59

4-chloro-2-[2-methoxy-5- (trifluoromethyl)phenyl]-5- methylphenolIntermediate B59 428.2 [M + H]⁺ B60

4-chloro-2-(2-methoxy-5- propan-2-ylphenyl)-5- methylphenol IntermediateB60 402.3 [M + H]⁺ B61

2-chloro-5-[2-fluoro-5- (morpholine-4- carbonyl)phenyl]-4-hydroxybenzonitrile Intermediate B61 472.2 [M + H]⁺ B62

[3-(5-chloro-2-hydroxy-4- methylphenyl)-4- fluorophenyl]-pyrrolidin-1-ylmethanone Intermediate B62 445.2 [M + H]⁺ B63

3-(5-chloro-2-hydroxy-4- methylphenyl)-N- cyclopropyl-4-fluoro-N-methylbenzamide Intermediate B63 445.3 [M + H]⁺ B64

3-(5-chloro-2-hydroxy-4- methylphenyl)-4-fluoro-N-(2- hydroxyethyl)-N-methylbenzamide Intermediate B64 449.2 [M + H]⁺ B65

4-[3-(5-Chloro-2-hydroxy-4- methylphenyl)-4- fluorobenzoyl]-1-methylpiperazin-2-one Intermediate B65 488.3 [M + H]⁺ B66

3-(5-chloro-2-hydroxy-4- methylphenyl)-N- cyclopentyl-4-fluoro-N-methylbenzamide Intermediate B66 473.3 [M + H]⁺ B67

4-Chloro-2-[2-fluoro-5- (oxolan-3- ylmethoxy)phenyl]-5- methylphenolIntermediate B67 448.3 [M + H]⁺ B68

3-(5-Chloro-2-hydroxy-4- methylphenyl)-4-fluoro-N- methyl-N-(thiophen-2-ylmethyl)benzamide Intermediate B68 501.3 [M + H]⁺ B69

[3-(5-chloro-2-hydroxy-4- methylphenyl)-4- fluorophenyl]-piperidin-1-ylmethanone Intermediate B69 459.3 [M + H]⁺ B70

3-(5-chloro-2-hydroxy-4- methylphenyl)-N- (cyclopropylmethyl)-4-fluoro-N-methylbenzamide Intermediate B70 459.3 [M + H]⁺ B71

3-(5-chloro-2-hydroxy-4- methylphenyl)-4-fluoro-N- methyl-N-(pyridin-2-ylmethyl)benzamide Intermediate B71 496.2 [M + H]⁺ B72

4-chloro-2-[2-fluoro-5-(oxan- 4-ylmethoxy)phenyl]-5- methylphenolIntermediate B72 462.2 [M + H]⁺ B73

3-(5-chloro-2-hydroxy-4- methylphenyl)-4-fluoro-N-(2- methoxyethyl)-N-methylbenzamide Intermediate B73 463.2 [M + H]⁺ B74

4-chloro-2-[2-fluoro-5- (oxolan-2- ylmethoxy)phenyl]-5- methylphenolIntermediate B74 448.2 [M + H]⁺ B75

2-[3-(5-chloro-2-hydroxy-4- methylphenyl)-4- fluorophenoxy]-N,N-dimethylacetamide Intermediate B75 449.2 [M + H]⁺ B76

1-[[3-(5-chloro-2-hydroxy-4- methylphenyl)-4- fluorophenyl]methyl]-4-methylpiperazine-2,5-dione Intermediate B76 488.2 [M + H]⁺ B77

7-(5-chloro-2-hydroxy-4- methylphenyl)-6-fluoro-3-methyl-1,3-benzoxazol-2-one Intermediate B77 419.1 [M + H]⁺ B78

N-[[3-(5-chloro-2-hydroxy-4- methylphenyl)-4- fluorophenyl]methyl]-2-methoxy-N-methylacetamide Intermediate B78 463.2 [M + H]⁺ B79

N-[[3-(5-chloro-2-hydroxy-4- methylphenyl)-4-fluorophenyl]methyl]cyclopro- pane-carboxamide Intermediate B79 445.1[M + H]⁺ B80

N-[[3-(5-chloro-2-hydroxy-4- methylphenyl)-4- fluorophenyl]methyl]-N-methylcyclopropane- carboxamide Intermediate B80 459.2 [M + H]⁺ B81

1-[[3-(5-chloro-2-hydroxy-4- methylphenyl)-4- fluorophenyl]methyl]-pyrrolidin-2-one Intermediate B81 445.1 [M + H]⁺ B82

3-[[3-(5-chloro-2-hydroxy-4- methylphenyl)-4- fluorophenyl]methyl]-1,3-oxazolidin-2-one Intermediated B82 447.1 [M + H]⁺ B83

N-[[3-(5-chloro-2-hydroxy-4- methylphenyl)-4- fluorophenyl]methyl]-2-methoxyacetamide Intermediate B83 449.2 [M + H]⁺ B84

2-chloro-5-(2-fluorophenyl)- 4-hydroxybenzonitrile Intermediate B84359.1 [M + H]⁺ B85

2-chloro-5-(3-fluorophenyl)- 4-hydroxybenzonitrile Intermediate B85359.1 [M + H]⁺ B86

3-(5-chloro-2-hydroxy-4- methylphenyl)-4-(trifluoro-methoxy)benzonitrile Intermediate B86 439.1 [M + H]⁺ B87

2-chloro-5-[2-fluoro-5- (oxolan-2- ylmethoxy)phenyl]-4-hydroxybenzonitrile Intermediate B87 459.2 [M + H]⁺ B88

2-chloro-5-(2-fluoro-3- methoxyphenyl)-4- hydroxybenzonitrileIntermediate B88 389.2 [M + H]⁺ B89

2-chloro-5-(2-fluoro-5- propan-2-yloxyphenyl)-4- hydroxybenzonitrileIntermediate B89 417.3 [M + H]⁺ B90

4-chloro-2-(2-fluoro-3- methoxyphenyl)-5- methylphenol Intermediate B90378.1 [M + H]⁺ B91

2-chloro-5-(2,3- difluorophenyl)-4- hydroxybenzonitrile Intermediate B91377.1 [M + H]⁺ B92

4-chloro-2-(5-cyclopropyl- oxy-2-fluorophenyl)-5- methylphenolIntermediate B92 404.2 [M + H]⁺ B93

2-chloro-5-(5-chloro-2- fluorophenyl)-4- hydroxybenzonitrileIntermediate B93 393.1 [M + H]⁺ B94

2-chloro-5-(2,5- difluorophenyl)-4- hydroxybenzonitrile Intermediate B94377.1 [M + H]⁺ B95

2-chloro-5-(5- cyclopropyloxy-2- fluorophenyl)-4- hydroxybenzonitrileIntermediate B95 415.2 [M + H]⁺ B96

2-chloro-5-[2-fluoro-5- (trifluoromethyl)phenyl]-4- hydroxybenzonitrileIntermediate B96 427.2 [M + H]⁺

The following Examples of type B were synthesized from the suitablebuilding blocks/intermediates and known3-(chloromethyl)-4-methyl-1H-1,2,4-triazol-5(4H)-one in analog toExample B1:

Building block/ Ex. Systematic Name intermediate MS, m/z B972-chloro-5-[2-fluoro-5-(trifluoromethoxy)-phenyl]-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3- yl)methoxy]benzonitrile  

2-chloro-5-[2-fluoro-5- (trifluorometh- oxy)phenyl]-4-hydroxybenzonitrile Intermediate B97 443.2 [M + H]⁺ B982-chloro-5-[2-fluoro-5-(2,2,2-trifluoro-ethoxy)phenyl]-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile  

2-chloro-5-[2-fluoro-5- (2,2,2-trifluoro- ethoxy)phenyl]-4-hydroxybenzonitrile Intermediate B98 457.2 [M + H]⁺

Example B223-[(4-Chloro-5-methyl-2-pyrazin-2-ylphenoxy)methyl]-4-methyl-1H-1,2,4-triazol-5-one

Step 1:5-(4-Chloro-2-iodo-5-methyl-phenoxymethyl)-4-methyl-2,4-dihydro-[1,2,4]triazol-3-one

The title compound was obtained in analogy to example B from4-chloro-2-iodo-5-methyl-phenol (900 mg, Intermediate B1, step 3) and3-(chloromethyl)-4-methyl-1H-1,2,4-triazol-5(4H)-one (35 mg. CAS:1338226-21-3) as an off white solid (1.07 g, 84%). MS (ESI): m/z=380.1[M+H]⁺.

Step 2:5-[(4-Chloro-2-iodo-5-methyl-phenoxy)methyl]-4-methyl-2-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-one

To a slurry of NaH (192 mg, 60% in mineral oil, CAS: 7646-69-7) inanhydrous DMF (10 mL) was added a solution of5-(4-chloro-2-iodo-5-methyl-phenoxymethyl)-4-methyl-2,4-dihydro-[1,2,4]triazol-3-one(1.21 g) in anhydrous DMF (20 mL) at rt and the resulting reactionmixture was stirred at rt for 30 min. Then,2-(trimethylsilyl)ethoxymethyl chloride (0.85 mL, CAS: 76513-69-4) wasadded dropwise to the reaction mixture and the mixture was stirred at rtfor 16 hours. The mixture was quenched with H₂O at 0° C. and the solventwas evaporated to dryness to get a residue which was dissolved in EtOAc(30 mL). The organic layer was washed with H₂O (30 mL) and brine (30mL), dried over Na₂SO₄, filtered and evaporated under reduced pressure.The product was purified by flash chromatography (5-25% EtOAc/hexane) togive the title compound as brown liquid (0.735 g, 45%). MS (ESI):m/z=509.8 [M+H]⁺.

Step 3:5-[(4-Chloro-5-methyl-2-pyrazin-2-yl-phenoxy)methyl]-4-methyl-2-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-one

A mixture of5-[(4-chloro-2-iodo-5-methyl-phenoxy)methyl]-4-methyl-2-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-one(312 mg), 2-(tributylstannyl)pyrazine (339 mg, CAS: 205371-27-3) inanhydrous DMF (6 mL) was purged with argon for 30 min. Then Pd(PPh₃)₄(14 mg, CAS: 14221-01-3) was added and the reaction mixture was heatedat 120° C. for 16 hours under an argon atmosphere. The reaction mixturewas filtered through celite bed. The filtrate was evaporated to get aresidue which was dissolved in EtOAc (40 mL). The organic layer waswashed with H₂O (40 mL) and brine (40 mL), dried over Na₂SO₄, filteredand evaporated under reduced pressure. The crude product was purified byflash chromatography over silica gel (15-35% EtOAc/hexane) to give thetitle compound as light yellow oil (0.187 g, 66%). MS (ESI): m/z=461.9[M+H]⁺.

Step 4:3-[(4-Chloro-5-methyl-2-pyrazin-2-ylphenoxy)methyl]-4-methyl-1H-1,2,4-triazol-5-one

To a solution of5-[(4-chloro-5-methyl-2-pyrazin-2-yl-phenoxy)methyl]-4-methyl-2-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-one(210 mg) in DCM (5 mL) was added TFA (2 mL, CAS: 76-05-1) and themixture was stirred at 25° C. for 3 hours. The solvent was evaporated toget a residue which was dissolved in EtOAc (30 mL) and washed withsaturated aqueous NaHCO₃ solution (25 mL), H₂O (25 mL) and brine (25mL). The organic layer was dried over Na₂SO₄, filtered and evaporatedunder reduced pressure. The resulting crude product was purified by prepHPLC (NH₄OAc/CH₃CN) to give the title compound as a white solid (0.052g, 35%). LC-MS: (ESI): m/z=332.1 [M+H]⁺.

Example B233-[(4-Chloro-5-methyl-2-pyrimidin-2-yl-phenoxy)methyl]-4-methyl-1H-1,2,4-triazol-5-one

To a solution of5-(4-chloro-2-iodo-5-methyl-phenoxymethyl)-4-methyl-2,4-dihydro-[1,2,4]triazol-3-one(150 mg, example B22, step) in dioxane (5 mL) were added2-tributylstannanyl-pyrimidine (364 mg, CAS: 153435-63-3) and Pd(PPh₃)₄(13 mg, CAS: 14221-01-3) and the reaction mixture was heated at 100° C.for 16 hours. The solvent was evaporated and the resulting crude productwas purified by prep HPLC (NH₄OAc/CH₃CN) to give the title compound as awhite solid (0.020 g, 15%). MS (ESI): m/z=332.3 [M+H]⁺.

Example B243-[[4-Chloro-5-methyl-2-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]phenoxy]methyl]4-methyl-1H-1,2,4-triazol-5-one

Step 1:3-(4-Chloro-2-iodo-5-methyl-phenoxymethyl)-5-methanesulfonyl-4-methyl-4H-[1,2,4]triazole

The title compound was obtained in analogy to example B1 from4-chloro-2-iodo-5-methyl-phenol (0.1 g, Intermediate B1, step 3) and3-(iodomethyl)-4-methyl-5-(methylsulfonyl)-4H-1,2,4-triazole (118 mg,prepared as described in US2008249151) as a colorless solid (0.145 g;88%). MS (ESI): m/z=441.95 [M+H]⁺.

Step 2:3-[[4-Chloro-5-methyl-2-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]phenoxy]methyl]-4-methyl-5-methylsulfonyl-1,2,4-triazole

The title compound was obtained in analogy to Intermediate B1, step 4,from3-(4-chloro-2-iodo-5-methyl-phenoxymethyl)-5-methanesulfonyl-4-methyl-4H-[1,2,4]triazole(0.066 g) and1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-pyrazole(0.049 g, CAS: 1025719-23-6) as a light brown gum (0.038 g: 55%). MS(ESI): m/z=464.08 [M+H]⁺.

Step 3:3-[[4-Chloro-5-methyl-2-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]phenoxy]methyl]-5-methoxy-4-methyl-1,2,4-triazole

To a solution of3-[[4-chloro-5-methyl-2-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]phenoxy]methyl]-4-methyl-5-methylsulfonyl-1,2,4-triazole(0.084 g) in MeOH (1 mL) was added 54M sodium methoxide solution in MeOH(134 μL, CAS: 124-414) and the solution was heated at reflux for 15minutes. The reaction mixture was poured on sat. aq. NH₄Cl solution andEtOAc and the layers were separated. The aqueous layer was extractedtwice with EtOAc. The organic layers were dried over MgSO₄, filtered,treated with silica gel and evaporated. The compound was purified bysilica gel chromatography on a 5 g column using an MPLC system elutingwith a gradient of DCM:MeOH (100/0 to 90/10) to give the title compoundas a colorless solid (0.054 g; 72%). MS (ESI): m/z=416.11 [M+H]⁺.

Step 4:3-[[4-Chloro-5-methyl-2-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one

To a solution of3-[[4-chloro-5-methyl-2-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]phenoxy]methyl]-5-methoxy-4-methyl-1,2,4-triazole(0.05 g) in AcOH (826 μL) was added HBr 48% in H₂O (261 μL) and theclear, colorless solution was stirred at reflux for 15 minutes. Then,the reaction mixture was evaporated. The residue was taken up in aq.sat. NaHCO₃ solution and EtOAc and the layers were separated. Theaqueous layer was extracted twice with EtOAc. The organic layers werewashed with brine, dried over MgSO₄, filtered and evaporated. Theresidue was purified by silica gel chromatography on a 5 g column usingan MPLC (ISCO) system eluting with a gradient of n-heptane:EtOAc (100/0to 0/100) to give the title compound as a colorless gum (0.036 g: 75%).MS (EST): m/z=402.10 [M+H]⁺.

Example B273-[[4-Chloro-5-methyl-2-(3-methylimidazol-4-yl)phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one

Step 1:5-[4-Chloro-5-methyl-2-(3-methyl-3H-imidazol-4-yl)-phenoxymethyl]-4-methyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,4-dihydro-[1,2,4]triazol-3-one

A mixture of5-(4-chloro-2-iodo-5-methyl-phenoxymethyl)-4-methyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,4-dihydro-[1,2,4]triazol-3-one(220 mg, example 22, step 2), 1-methyl-1H-imidazole-5-boronic acidpinacol ester (180 mg, CAS: 942070-72-6), potassium phosphate tribasic(183 mg, CAS: 7778-53-2), tricyclohexyl phosphine (2 mg, CAS: 2622-14-2)in dioxane (4 mL) and H₂O (20 mL) was purged with argon for 20 min. Thentris(dibenzylideneacetone)dipalladium(0) (4 mg. CAS: 52409-22-0) wasadded and the mixture was heated at 120° C. in microwave oven for 1hour. The mixture was filtered through a celite bed. The filtrate wasevaporated to get a residue which was dissolved in EtOAc (30 mL) andwashed with H₂O (40 mL) and brine (40 mL). The organic layer was driedover Na₂SO₄, filtered and evaporated under reduced pressure. Theresulting crude material was purified by flash chromatography oversilica gel (1-5% MeOH/DCM) to give the title compound as a brown liquid(180 mg, 90%). MS (ESI): m/z=464.4 [M+H]⁺.

Step 2:3-[[4-Chloro-5-methyl-2-(3-methylimidazol-4-yl)phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one

The title compound was obtained in analogy to Intermediate B22, step 4,from5-[4-chloro-5-methyl-2-(3-methyl-3H-imidazol-4-yl)-phenoxymethyl]-4-methyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,4-dihydro-[1,2,4]triazol-3-one(0.160 g) as an off white solid (28 mg, 24%). MS (ESI): m/z=334.0[M+H]⁺.

Example B283-[[4-Chloro-2-(1H-imidazol-5-yl)-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one

Step 1: 5-Iodo-1-trityl-1H-imidazole

To a solution of 4-iodo-1H-imidazole (2.05 g, CAS: 71759-89-2) andtrityl chloride (4.4 g, CAS: 76-83-5) in DMF (35 mL) was addedtriethylamine (3.04 mL, CAS: 121-44-8) at 0° C. The reaction mixture wasslowly warmed to rt and was stirred for 48 hours. The reaction mixturewas then poured into H₂O (150 mL). The solid was filtered, washed withH₂O (60 mL) and dried under reduced pressure. The resulting crudematerial was purified by flash chromatography using silica gel (EtOAc)to give the title compound as a white solid (4.3 g, 93%). RI 0.50 (10%EtOAc/hexane).

Step 2: 5-Tributylstannanyl-1-trityl-1H-imidazole

To a solution of 5-iodo-1-trityl-1H-imidazole (2.02 g) in DCM (50 mL)was added ethyl magnesium bromide (1.8 mL, 3M in diethyl ether, CAS:925-90-6). The reaction was stirred under argon atmosphere at rt for 1hour. Tributyltin chloride (1.5 mL, CAS: 1461-22-9) was added to thereaction mixture and the resulting mixture was stirred at rt overnight.The reaction mixture was diluted with DCM (100 mL) and successivelywashed with saturated aqueous NH₄Cl (100 mL), H₂O (100 mL) and brine(100 mL). The organic phase was dried over Na₂SO₄, filtered andevaporated to give the title compound as a white solid (2.7 g, 97%)which was used in the next step without further purification. R_(f)=0.60(10% EtOAc/hexane).

Step 3:5-[4-Chloro-5-methyl-2-(3-trityl-3H-imidazol-4-yl)-phenoxymethyl]-4-methyl-2,4-dihydro-[1,2,4]triazol-3-one

The title compound was obtained in analogy to example 23, from5-(4-chloro-2-iodo-5-methyl-phenoxymethyl)-4-methyl-2,4-dihydro-[1,2,4]triazol-3-one(example 22, step 1) and 5-tributylstannanyl-1-trityl-1H-imidazole as ayellow solid. MS (EI): m/z=562.3 [M+H]⁺.

Step 4:3-[[4-Chloro-2-(1H-imidazol-5-yl)-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one

To a solution of5-[4-chloro-5-methyl-2-(3-trityl-3H-imidazol-4-yl)-phenoxymethyl]-4-methyl-2,4-dihydro-[1,2,4]triazol-3-one(80 mg) in DCM (5 mL) was added HCl (0.5 mL, 4N in dioxane, CAS:7647-01-0) at 25° C. and the resulting mixture was stirred for 4 hours.The reaction mixture was evaporated and the resulting material waspurified by flash chromatography using silica gel (10% MeOH/DCM) to givethe title compound as a white solid (12 mg, 26%). MS (ESI): m/z=320.2[M+H]⁺.

Example B293-[[4-Chloro-5-methyl-2-(1,3-oxazol-2-yl)phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one

The title compound was prepared in analogy to example B23 from5-(4-chloro-2-iodo-5-methyl-phenoxymethyl)-4-methyl-2,4-dihydro-[1,2,4]triazol-3-one(150 mg, example B22, step 1) and 2-tributylstannanyloxazole (207 mg,CAS: 145214-05-7). The compound was obtained as white solid (9 mg, 7%).MS (ESI): m/z=320.9 [M+H]⁺.

Example B342-Chloro-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]-5-[3-(H-pyrazol-3-yl)phenyl]benzonitrile

Step 1: 3′-Acetyl-4-chloro-6-hydroxy-biphenyl-3-carbonitrile and3′-acetyl-4-chloro-6-methoxymethoxy-biphenyl-3-carbonitrile

The title compound was prepared in analogy to Intermediate B31, step 3,from 5-bromo-2-chloro-4-methoxymethoxy-benzonitrile (Intermediate B31,step 2) (1.0 g) and 3-acetyl-phenyl boronic acid (886 mg, CAS:204841-194)). Note that in this case the MOM-protected phenol was usedas a starting material.

These conditions provided the MOM protected phenol3′-acetyl-4-chloro-6-methoxymethoxy-biphenyl-3-carbonitrile (270 mg,24%, ¹H-NMR (400 MHz, DMSO-D6): 2.63 (s, 3H), 3.36 (s, 3H), 5.37 (s,2H), 7.55 (s, 1H), 7.62 (t, 1H, J=7.6), 7.80 (d, 1H, J=7.6), 7.98 (d,1H, J=7.6), 8.03 (s, 1H), 8.10 (s, 1H)), as well as the free phenol3′-acetyl-4-chloro-6-hydroxy-biphenyl-3-carbonitrile (190 mg, 19%):¹H-NMR (400 MHz, DMSO-D6): 2.63 (s, 3H), 7.19 (s, 1H), 7.53-7.63 (m,—1H), 7.83 (d, 1H, J=8): 7.95 (d, 1H, J=7.8), 7.97 (s, 1H), 8.11 (s,1H), 11.48 (s, 1H).

Note that depending on the reaction conditions, the MOM group may bepartially lost in this reaction to give the free phenol3′-acetyl-4-chloro-6-hydroxy-biphenyl-3-carbonitrile. This material canbe subjected to step 2 below to re-introduce the MOM group. The MOMprotected material from step 1 can be used directly in step 3.

Step 2: 3′-Acetyl-4-chloro-6-methoxymethoxy-biphenyl-3-carbonitrile

The title compound was prepared in analogy to Intermediate B31, step 2,from 3′-acetyl-4-chloro-6-hydroxy-biphenyl-3-carbonitrile (250 mg) byreaction with NaH (44 mg, 60% in mineral oil) and MOM-Cl (0.14 mL) andwas obtained as an off white solid (183 mg, 63%). ¹H-NMR (400 MHz,DMSO-D6): 2.63 (s, 3H), 3.36 (s, 3H), 5.37 (s, 2H), 7.55 (s, 1H), 7.62(t, 1H, J=7.6), 7.80 (d, 1H, J=7.6), 7.98 (d, 1H, J=7.6), 8.04 (s, 1H),8.10 (s, 1H).

Step 3:4-Chloro-3′-((E)-3-dimethylamino-acryloyl)-6-methoxymethoxy-biphenyl-3-carbonitrile

A solution of3′-acetyl-4-chloro-6-methoxymethoxy-biphenyl-3-carbonitrile (180 mg) inDMF-DMA (2.5 mL) was heated to 80° C. for 16 h. The reaction mixture wascooled to 25° C. and all volatiles were evaporated under reducedpressure. The remaining residue was purified by column chromatographyover silica gel (80-100% EtOAc/hexane) to afford the title compound (140mg, 66%) as an off white solid. MS (ESI): m/z=370.9 [M+H]⁺.

Step 4:3′-(1-tert-Butyl-1H-pyrazol-3-yl)-4-chloro-6-methoxymethoxy-biphenyl-3-carbonitrile

To a solution of4-chloro-3′-((E)-3-dimethylamino-acryloyl)-6-methoxymethoxy-biphenyl-3-carbonitrile(140 mg) in EtOH (20 mL) was added tert-butyl-hydrazine (70.37 mg, CAS:7400-27-3) at 0° C. The reaction mixture was heated to reflux for 12 h.The mixture was then cooled to 25° C. and all volatiles were removedunder reduced pressure. The residue was purified by columnchromatography over silica gel (10-15% EtOAc/hexane) to obtain the titlecompound (110 mg, 73%) as an off white solid. MS (ESI): m/z=396.0[M+H]⁺.

Step 5:3′-(1-tert-Butyl-1H-pyrazol-3-yl)-4-chloro-6-hydroxy-biphenyl-3-carbonitrile

To a solution of3′-(1-tert-butyl-1H-pyrazol-3-yl)-4-chloro-6-methoxymethoxy-biphenyl-3-carbonitrile(110 mg) in anhydrous DCM (10 mL) was added HCl in dioxane (1 mL) at 0°C. and the reaction mixture was stirred at 25° C. for 32 h. The mixturewas diluted with DCM (30 mL) and was washed with sat. NaHCO₃ solutionand brine, dried over Na₂SO₄ and concentrated. The residue was purifiedby column chromatography over silica gel (1-2% MeOH/DCM) to afford thetitle compound (45 mg, 46%) as an off white solid. MS (ESI): m/z=352.2[M+H]⁺.

Step 6:3′-(1-tert-Butyl-1H-pyrazol-3-yl)-4-chloro-6-(4-methyl-5-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-ylmethoxy)-biphenyl-3-carbonitrile

The title compound was obtained in analogy to example B1 from3′-(1-tert-butyl-1H-pyrazol-3-yl)-4-chloro-6-hydroxy-biphenyl-3-carbonitrile(80 mg) and 3-(chloromethyl)-4-methyl-1H-1,2,4-triazol-5(4H)-one (34 mg)as an off white solid (45 mg, 43%). MS (ESI): m/z=463.0 [M+H]⁺.

Step 7:2-Chloro-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]-5-[3-(1H-pyrazol-3-yl)phenyl]benzonitrile

A solution of3′-(1-tert-butyl-1H-pyrazol-3-yl)-4-chloro-6-(4-methyl-5-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-ylmethoxy)-biphenyl-3-carbonitrile(45 mg) in formic acid (4 mL) was heated to 85° C. for 6 h. Then, allvolatiles were removed and the residue was diluted with DCM (20 mL) andwashed with water and brine, dried over Na₂SO₄ and concentrated. Theresulting material was purified by column chromatography over silica gel(2-3% MeOH/DCM) to afford the title compound (15 mg, 37%) as an offwhite solid. MS (ESI): m/z=407.2 [M+H]⁺.

Example B433-[5-Chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]benzoicacid

Methyl3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]benzoate(36.0 mg, example B42) was suspended in THF (1.5 mL) at r. MeOH wasadded dropwise until everything was dissolved. Then, a solution oflithiumhydroxide monohydrate (11.7 mg) in water (280 μL) was addeddropwise. A small amount of white solid precipitated. Again, MeOH wasadded dropwise until everything was in solution. The colorless solutionwas then stirred at overnight. The volatiles were removed and theremaining residue was dissolved in water. The pH was adjusted to 2 byaddition of 1N HCl. The precipitate was filtered off, washed with asmall amount of water and dried to obtain the title compound as whitesolid (31 mg, 89%). MS (ESI): m/z=374.1[M+H]⁺.

The following examples were synthesized in analogy to Example B43:

Ex. Systematic Name Starting Material MS, m/z B47

Methyl 3-[[3-[5-chloro-4- methyl-2-[(4-methyl-5-oxo- 1H-1,2,4-triazol-3-yl)methoxy]phenyl]benzoyl]- amino]propanoate Example B44 445.2 [M + H]⁺B48

Ethyl 2-[[3-[5-chloro-4- methyl-2-[(4-methyl-5-oxo- 1H-1,2,4-triazol-3-yl)methoxy]phenyl]benzoyl]- amino]acetate Example B46 431.1 [M + H]⁺ B50

Methyl 3-[5-chloro-4-methyl- 2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]- 4-methylbenzoate Example B49 388.2 [M +H]⁺

Example B453-[5-Chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-N-(2-hydroxyethyl)-N-methylbenzamide

3-[5-Chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]benzoicacid (23.0 mg, example B43) was dissolved in N,N-dimethylformamide (0.5mL). Then, HATU (35.1 mg) and Hunig's base (19.9 mg, 26.9 μL) were addedat rt, followed by a solution of 2-(methylamino)ethanol (6.47 mg) inN,N-dimethylformamide (0.5 mL). The light yellow solution was stirred atrt for 2 h. The reaction mixture was diluted with sat. NH₄Cl solutionand was extracted with EtOAc. The combined organic extracts were washedwith water and brine, dried over Na₂SO₄ and evaporated. The residue waspurified by HPLC (Gemini NX column, acetonitrile/water (containing 0.05%formic acid) 85:15) to obtain the title compound as a white solid (10mg, 38%). MS (ESI): m/z=431.2 [M+H]⁺.

Example B513-[5-Chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-N,N,4-trimethylbenzamide

The title compound was obtained in analogy to example B47 from3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-4-methylbenzoicacid (23 mg, Example B50) and dimethylamine hydrochloride (6.77 mg) as awhite solid (14 mg, 57%). MS (ESI): m/z=415.2 [M+H]⁺.

Examples C: Compounds with Pyridazinone Head Groups Example C13-[(4-Chloro-5-methyl-2-propan-2-ylphenoxy)methyl]-1H-pyridazin-6-one

To a solution of3-chloro-6-[(4-chloro-2-isopropyl-5-methyl-phenoxy)methyl]pyridazine (60mg, Intermediate C1-A) in EtOH (3 mL) was added aqueous 3M NaOH (0.642mL) and the reaction mixture was heated at reflux for 16 hours. Thereaction mixture was poured into H₂O and EtOAc and the layers wereseparated. The organic layer was dried over Na₂SO₄, filtered andconcentrated in vacuo. The material was purified by flash chromatographyover silica gel (0-3% MeOH/DCM) to give to give the title compound as anoff-white solid (0.005 g, 9%). MS (ESI): m/z=293.11 [M]⁺.

Example C23-[(4-Chloro-2-cyclopropyl-5-methylphenoxy)methyl]-1H-pyridazin-6-one

A solution of3-chloro-6-(4-chloro-2-cyclopropyl-5-methyl-phenoxymethyl)-pyridazine(45 mg, Intermediate C2-A) was refluxed in glacial acetic acid (5 mL) at120° C. for 16 hours. Then, the solvent was removed under reducedpressure. The residue was dissolved in DCM and the organic part waswashed with saturated solution of NaHCO₃ and brine, dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The productwas purified by prep. HPLC (NH₄OAc/CH₃CN) to give the title product as awhite solid (30 mg, 71%). MS: (ESI): m/z=291.4 [M+H]⁺.

The following examples were synthesized from the suitable buildingblocks/intermediates in analogy to example C2:

Building block/ Ex. Systematic Name intermediate MS, m/z C33-[(4-chloro-5-fluoro-2-propan-2- ylphenoxy)methyl]-1H-pyridazin-6-one  

3-chloro-6-(4-chloro-5- fluoro-2-isopropyl- phenoxymethyl)-pyridazineIntermediate C3-A 297.2 [M + H]⁺ C4 3-[(5-chloro-4-methyl-2-propan-2-ylphenoxy)methyl]-1H-pyridazin-6-one  

3-chloro-6-(5-chloro-2- isopropyl-4-methyl- phenoxymethyl)-pyridazineIntermediate C4-A 293.2 [M + H]⁺ C5 3-[(4-chloro-2-cyclobutyl-5-methylphenoxy)methyl]-1H-pyridazin-6-one  

3-chloro-6-(4-chloro-2- cyclobutyl-5-methyl- phenoxymethyl)-pyridazineIntermediate C5-A 305.2 [M + H]⁺ C6 3-[(4-chloro-2-cyclohexyl-5-methylphenoxy)methyl]-1H-pyridazin-6-one  

3-chloro-6-(4-chloro-2- cyclohexyl-5-methyl- phenoxymethyl)-pyridazineIntermediate C6-A 333.3 [M + H]⁺ C7 3-[[4-chloro-5-methyl-2-(oxan-4-yl)phenoxy]methyl]-1H-pyridazin-6-one  

3-chloro-6-[4-chloro-5- methyl-2-(tetrahydro-pyran-4-yl)-phenoxymethyl]- pyridazine Intermediate C7-A 335.1 [M + H]⁺ C83-[(2-tert-butyl-4-chloro-5- methylphenoxy)methyl]-1H-pyridazin-6-one  

3-(2-tert-butyl-4-chloro-5- methyl-phenoxymethyl)-6- chloro-pyridazineIntermediate C8-A 307.3 [M + H]⁺ C9 2-[5-chloro-4-methyl-2-[(6-oxo-1H-pyridazin-3-yl)methoxy]phenyl]-2- methylpropanenitrile  

2-[5-chloro-2-(6-chloro- pyridazin-3-ylmethoxy)-4-methyl-phenyl]-2-methyl- propionitrile Intermediate C9-A 318.0 [M + H]⁺

The following examples of type C were synthesized from the suitablebuilding blocks/intermediates in analogy to Example C2:

Building block/ Ex. Systematic Name intermediate MS, m/z C10

3-chloro-6-[[4-chloro-2-(2- methoxypyridin-3-yl)-5-methylphenoxy]methyl] pyridazine Intermediate C10-A 358.2 [M + H]⁺ C11

3-chloro-6-[[4-chloro-2-(2- methoxypyridin-3-yl)-5-methylphenoxy]methyl]- pyridazine Intermediate C10-A 344.1 [M + H]⁺ C12

2-chloro-4-[(6- chloropyridazin-3- yl)methoxy]-5- phenylbenzonitrileIntermediate C12-A 338.1 [M + H]⁺ C13

4-tert-butyl-5-[(6- chloropyridazin-3- yl)methoxy]-2- methylbenzonitrileIntermediate C13-A 298.2 [M + H]⁺ C14

2-chloro-4-[(6-chloro- pyridazin-3-yl)methoxy]-5- (5-cyclopropyloxy-2-fluorophenyl)benzonitrile Intermediate C14-A 412.1 [M + H]⁺

Examples D: Compounds with Head Groups Related to Indazole, Aza-Indazoleand Similar Example D23-[(4-Chloro-5-methyl-2-propan-2-ylphenoxy)methyl]-1H-indazole

To a solution of 4-chloro-2-isopropyl-5-methylphenol (0.15 g, CAS:89-68-9) in DMF (1.5 mL) was added sodium hydride (42.5 mg, 55-60% inmineral oil) and the mixture was stirred at rt for 15 minutes. Asuspension of tert-butyl 3-(bromomethyl)-1H-indazole-1-carboxylate (253mg CAS: 174180-42-8) in DMF (2.5 mL) was then added dropwise. Afterstirring at rt for 2.5 hours, the reaction mixture was poured on amixture of saturated aqueous NH₄Cl solution and ethyl acetate and thelayers were separated. The aqueous layer was extracted twice with ethylacetate. The combined organic layers were washed twice with water andonce with brine, dried over MgSO₄, filtered, and evaporated. The residuewas purified by silica gel chromatography using an MPLC system (elutingwith a gradient of n-heptane:ethyl acetate from 100/0 to 60/40). Theresulting light brown oil (0.157 g) was dissolved in dichloromethane(1.5 mL). The solution was cooled to 0° C. and trifluoroacetic acid(1.85 g, 1.25 mL) was added. After stirring at rt for 1.25 hours, thereaction mixture was poured into a mixture of saturated aqueous NaHCO₃solution and dichloromethane and the layers were separated. The aqueouslayer was extracted twice with dichloromethane. The combined organiclayers were washed once with brine, dried over MgSO₄, filtered andevaporated. The residue was purified by silica gel chromatography usingan MPLC system (eluting with a gradient of n-heptane:ethyl acetate from100/0 to 60/40) to afford the title compound as colorless oil (48 mg;19%). MS (ESI): m/z=315.13 [M+H]⁺.

Example D33-[(2-tert-Butyl-4-chloro-5-methylphenoxy)methyl]-1H-pyrazolo[3,4-b]pyridine

To a solution of Intermediate D3-A (85.1 mg) in dioxane (3 mL) was added4N HCl in dioxane (495 μl) and the solution was stirred at rt. A whitesolid precipitated and the suspension was stirred at rt overnight. Thenadditional 4N HCl in dioxane (495 μl) was added and after 4 h at rtagain additional 4N HCl in dioxane (495 μl) was added and the mixturewas stirred at rt for another 2 days. The white suspension was pouredonto saturated NaHCO₃ solution and the resulting mixture was extractedwith DCM. The combined organic layers were dried over Na₂SO₄ andevaporated. The residue was purified by chromatography (10 g silica gel;heptane/EtOAc 90/10-70/30) to afford the title compound (54 mg, 83%) asa white solid. MS (ESI): m/z=330.2 [M+H]⁺.

The following examples were synthesized in analogy to example D3.

Inter- MS, Ex. Systematic Name mediate m/z D4

Inter- mediate D4-A 321.2 [M + H]⁺ D5

Inter- mediate D5-A 341.2 [M + H]⁺

Example D63-[(2-tert-Butyl-4-chloro-5-methylphenoxy)methyl]-6-fluoro-1H-pyrazolo[3,4-b]pyridine

A solution of Intermediate D6-A (55.1 mg) in a mixture of DCM (1 mL) andtrifluoroacetic acid (0.4 mL) was stirred at rt for 1 h. Then, thesolution was diluted with DCM and it was slowly added to saturatedNa₂CO₃ solution. The mixture was extracted with DCM and the combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered, andevaporated. The remaining residue was purified by chromatography (5 gsilica gel; DCM/MeOH 98:2) to obtain the title compound (40 mg, 94%) asa white solid. MS (ESI): m/z=348.1 [M+H]⁺.

The following examples were synthesized in analogy to example D6.

Ex. Systematic Name Intermediate MS, m/z D9

Intermediate D9-A 374.2 [M + H]⁺ D10

Intermediate D10-A 373.2 [M + H]⁺ D12

Intermediate D12-A 352.1 [M + H]⁺ D16

Intermediate D16-A 451.2 [M + H]⁺ D18

Intermediate D18-A 421.2 [M + H]⁺ D39

Intermediate D39-A 508.2 [M + H]⁺ D40

Intermediate D40-A 483.16 [M + H]⁺ D41

Intermediate D41-A 507.2 [M + H]⁺ D42

Intermediate D42-A 465.14 [M + H]⁺ D43

Intermediate D43-A 476.12 [M + H]⁺ D45

Intermediate D45-A 360.1 [M + H]⁺

Example D72-[[3-[(2-tert-Buty-4-chloro-&-methylphenoxy)methyl]-1H-pyrazolo[3,4-b]pyridin-6-yl]amino]ethanol

A solution of Intermediate D6-A (99.9 mg) and ethanolamine (136 mg, 135μL) in N-methyl-2-pyrrolidinone (1.8 mL) was heated to 95° C. overnight.The solution was cooled to rt, diluted with half saturated brine and themixture was extracted with EtOAc. The combined organic layers werewashed with water and brine, dried over Na₂SO₄ and evaporated. The crudematerial was purified by chromatography (20 g silica gel; DCM/MeOH100/0-95/5) to obtain a white solid which was further purified by prep.HPLC to afford the title compound (38 mg, 44%) as a white solid. MS(ESI): m/z=389.2 [M+H]⁺.

Example D82-[[3-[(2-tert-Butyl-4-chloro-5-methylphenoxy)methyl]-1H-pyrazolo[3,4-b]pyridin-6-yl]-methylamino]ethanol

A solution of Intermediate D6-A (99.9 mg) and 2-(methylamino)ethanol(167 mg, 178 μl) in N-methyl-2-pyrrolidinone (1.8 mL) was heated to 50°C. for 5 h. The solution was cooled to rt, diluted with half saturatedbrine and extracted with EtOAc. The combined organic layers were washedwith water and brine, dried over Na₂SO₄ and evaporated. The residue wasdissolved in DCM (2 mL) and trifluoroacetic acid (0.4 mL) was added. Thesolution was stirred at rt for 30 min and was then poured onto saturatedNa₂CO₃ solution and the mixture was extracted with DCM. The combinedorganic layers were washed with brine, dried over Na₂SO₄ and evaporated.The residue was purified by column chromatography (5 g silica gel;DCM/MeOH 98/2-95/5) to afford the title compound (41 mg, 46%) as a whitesolid. MS (ESI): m/z=403.2 [M+H]⁺.

The following examples were synthesized in analogy to example D8.

Ex. Systematic Name Intermediate/Amine MS, m/z D11

Intermediate D12-A and 2-aminoethanol 393.2 [M + H]⁺ D14

Intermediate D12-A and 2-(methylamino)ethanol 407.2 [M + H]⁺

Example D132-[[3-[(2-t-Butyl-4-chloro-&-methylphenoxy)methyl]-1H-pyrazolo[3,4-b]pyridin-6-yl]oxy]ethanol

Step 1:3-[(2-tert-Butyl-4-chloro-5-methyl-phenoxy)methyl]-6-fluoro-1-trityl-pyrazolo[34-b]pyridine

Sodium hydride (23.2 mg, 55% in mineral oil) was suspended in DMF (1 mL)and a solution of3-[(2-tert-butyl-4-chloro-5-methylphenoxy)methyl]-6-fluoro-1H-pyrazolo[3,4-b]pyridine(148 mg, example D6) in DMF (1 mL) was added dropwise at 0° C. Theresulting brown suspension was stirred at 0° C. for 10 min and then atrt for 20 min. A solution of trityl chloride(=[chloro(diphenyl)methyl]benzene) (125 mg) in DMF (1 mL) was then addedat 0° C. and the reaction mixture was stirred at rt overnight. Water wasadded carefully and the mixture was extracted with EtOAc. The combinedorganic layers were washed with water and brine, dried over Na₂SO₄ andevaporated. The residue was purified by chromatography (20 g silica gel;heptane/EtOAc 98/2-90/10) to obtain the title compound (186 mg, 74%) asa white solid. ¹H-NMR (300 MHz, CDCl₃): 1.29 (s, 9H), 2.25 (s, 3H), 5.34(s, 2H), 6.64 (dd, 1H), 6.92 (s, 1H), 7.19 (s, 1H), 7.20-7.35 (m, ˜15H),8.10 (dd, 1H).

Step 2:3-[(2-tert-Butyl-4-chloro-5-methyl-phenoxy)methyl]-6-(2-tetrahydropyran-2-yloxyethoxy)-1-trityl-pyrazolo[3,4-b]pyridine

Sodium hydride (7.68 mg, 55% in mineral oil) was suspended in DMA (1mL). Then, a solution of 2-(tetrahydro-2H-pyran-2-yloxy)ethanol (25.7mg, 23.9 μL, CAS: 2162-314) in DMA (1.5 mL) was added dropwise at 0° C.and the resulting suspension was stirred at rt for 30 min. Then, a whiteturbid solution of3-[(2-tert-butyl-4-chloro-5-methyl-phenoxy)methyl]-6-fluoro-1-trityl-pyrazolo[3,4-b]pyridine(83.2 mg) in DMA (1.5 ml) was added dropwise and the reaction mixturewas stirred at rt for 3 h. The mixture was carefully diluted with waterand was extracted with EtOAc. The combined organic layers were washedwith water and brine, dried over Na₂SO₄ and evaporated. The residue waspurified by flash chromatography (10 g silica gel; heptane/EtOAc98/2-95/5) to obtain the title compound (91 mg, 90%) as a colorless oil.¹H-NMR (300 MHz, CDCl₃): 1.29 (s, ˜9H); 1.45-1.88 (m, ˜6H), 2.24 (s,3H), 3.35-3.51 (m, 2H), 3.60-3.70 (m, 1H), 3.75-3.88 (m, 2H), 4.50 (m,1H), 5.30 (s, 2H), 6.50 (d, 1H, J=8.4), 6.94 (s, 1H), 7.18 (s, 1H),7.20-7.30 (m, ˜15H), 7.86 (d, 1H, J=8.7).

Step 3:2-[[3-[(2-tert-Butyl-4-chloro-5-methylphenoxy)methyl]-1H-pyrazolo[3,4-b]pyridin-6-yl]oxy]ethanol

To a solution of3-[(2-tert-butyl-4-chloro-5-methyl-phenoxy)methyl]-6-(2-tetrahydropyran-2-yloxyethoxy)-1-trityl-pyrazolo[3,4-b]pyridine(83.8 mg) in DCM (1.5 mL) was added trifluoroacetic acid (0.4 mL)dropwise and the mixture was stirred at rt for 30 min. The reactionmixture was diluted with DCM and was carefully added to saturated Na₂CO₃solution. The resulting mixture was extracted with DCM and the combinedextracts were washed with saturated Na₂CO₃ solution and brine, driedover Na₂SO₄, and evaporated. The residue was purified by chromatography(10 g silica gel; heptane/EtOAc 90/10-50/50) to obtain the titlecompound (36 mg, 79%) as white solid. MS (ESI): m/z=390.2 [M+H]⁺.

Example D153-[[3-[(2-tert-Butyl-4-chloro-5-methylphenoxy)methyl]-1H-pyrazolo[3,4-b]pyridin-6-yl]oxy]propane-1,2-diol

The title compound was prepared from3-[(2-tert-butyl-4-chloro-5-methylphenoxy)methyl]-6-fluoro-1H-pyrazolo[3,4-b]pyridine(example D6) in analogy to example D13 using(2,2-dimethyl-1,3-dioxolan-4-yl)methanol instead of2-(tetrahydro-2H-pyran-2-yloxy)ethanol in step 2 and was obtained as awhite solid. MS (ESI): m/z=420.2 [M+H]⁺.

Example D17[3-[5-Chloro-4-methyl-2-(1H-pyrazolo[3,4-b]pyridin-3-ylmethoxy)phenyl]phenyl]-morpholin-4-ylmethanone

A suspension of Intermediate B10 (40.1 mg), tert-butyl3-(bromomethyl)pyrazolo[3,4-b]pyridine-1-carboxylate (37.8 mg, CAS:174180-76-8) and potassium carbonate (41.7 mg) in acetone (1.5 mL) washeated to 50° C. for 5.5 h. The reaction mixture was cooled to rt,diluted with water and extracted with EtOAc. The combined organic layerswere washed with brine, dried over Na₂SO₄ and evaporated. The residuewas dissolved in DCM (2 mL) and trifluoroacetic acid (0.2 mL) was addedand the solution was stirred at rt for 2 h. The reaction mixture wasquenched carefully by addition of saturated Na₂CO₃ solution and wasextracted with DCM. The combined organic layers were washed with brine,dried over Na₂SO₄ and evaporated. The residue was purified bychromatography (10 g silica gel, heptane/EtOAc 70/30-0/100) to obtainthe title compound (40 mg, 710) as white solid. MS (ESI):m/z=463.2[M+H]⁺.

The following examples were synthesized in analogy to Example D17.

Ex. Systematic Name Building blocks MS, m/z D1

tert-butyl 3-(bromomethyl)- 1H-indazole-1-carboxylate (CAS 174180-42-8)and Intermediate A15 359.14 [M + H]⁺ D19

tert-butyl 3- (bromomethyl)pyrazolo[3,4- b]pyridine-1-carboxylate (CAS:174180-76-8) and Intermediate B36 437.2 [M + H]⁺ D20

tert-butyl 3- (bromomethyl)pyrazolo[3,4- b]pyridine-1-carboxylate (CAS:174180-76-8) and Intermediate B53 381.1 [M + H]⁺ D21

tert-butyl 3- (bromomethyl)pyrazolo[3,4- b]pyridine-1-carboxylate (CAS:174180-76-8) and Intermediate B38 439.2 [M + H]⁺ D22

tert-butyl 3- (bromomethyl)pyrazolo[3,4- b]pyridine-1-carboxylate (CAS:174180-76-8) and Intermediate B40 481.2 [M + H]⁺ D23

tert-butyl 3- (bromomethyl)pyrazolo[4,3- b]pyridine-1-carboxylate (CAS:194278-49-4, prepared according to J. Med. Chem. 1997, 40, 2709) and2-tert-butyl-4-chloro-5- methyl-phenol (CAS: 30894-16-7) 330.2 [M + H]⁺D24

tert-butyl 3- (bromomethyl)pyrazolo[4,3- b]pyridine-1-carboxylate (CAS:194278-49-4) and Intermediate B12 421.2 [M + H]⁺ D25

tert-butyl 3- (bromomethyl)pyrazolo[4,3- b]pyridine-1-carboxylate (CAS:194278-49-4) and Intermediate A2 334.2 [M + H]⁺ D28

tert-butyl 3- (bromomethyl)pyrazolo[4,3- b]pyridine-1-carboxylate (CAS:194278-49-4) and Intermediate B38 439.2 [M + H]⁺ D48

tert-butyl 3- (bromomethyl)pyrazolo[3,4- b]pyridine-1-carboxylate (CAS:174180-76-8) and Intermediate A17 321.2 [M + H]⁺

Example D262-[[3-[(2-tert-Butyl-4-chloro-5-methylphenoxy)methyl]-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-methylamino]ethanol

Step 1:3-(2-tert-Butyl-4-chloro-5-methyl-phenoxymethyl)-1-(4-methoxy-benzyl)-6-methylsulfanyl-1H-pyrazolo[3,4-]pyrimidine

To a solution of 2-tert-butyl-4-chloro-5-methyl-phenol (851 mg, CAS:30894-16-7) in anhydrous DMF (50 mL) were added Cs₂CO₃ (1.61 g) and TBAI(122 mg) at 25° C. and the reaction mixture was stirred at 25° C. for 15min. Then, a solution of3-bromomethyl-1-(4-methoxy-benzyl)-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine(1.26 g, Intermediate D26-B) in anhydrous DMF (10 mL) was added at 25°C. and the reaction mixture was stirred for 16 h at 25° C. The mixturewas filtered and the filtrate was diluted with EtOAc and washed withwater and brine. The organic layer was dried over Na₂SO₄, filtered andevaporated under reduced pressure. The residue was purified by columnchromatography over silica gel (5-10% EtOAc in hexane) to afford thetitle compound (1.41 g, 86%) as an off white solid. MS (ESI): m/z=497.1[M+H]⁺.

Step 2:3-(2-tert-Butyl-4-chloro-5-methyl-phenoxymethyl)-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine

A solution of3-(2-tert-butyl-4-chloro-5-methyl-phenoxymethyl)-1-(4-methoxy-benzyl)-6-methylsulfanyl-1H-pyrazolo[3,4-]pyrimidine(1.4 g) in 30% HBr in AcOH (30 mL) was heated to 80° C. for 2 h. Thereaction mixture was cooled to 25° C., diluted with EtOAc and washedwith saturated NaHCO₃ solution and brine. The organic layer was driedover Na₂SO₄, filtered and evaporated under reduced pressure. The residuewas purified by column chromatography over silica gel (15-50% EtOAc inhexane) to afford the title compound (750 mg, 71%) as an off whitesolid. MS (ESI): m/z=377.2 [M+H]⁺.

Step 3:3-(2-tert-Butyl-4-chloro-5-methyl-phenoxymethyl)-6-methanesulfonyl-1H-pyrazolo[3,4-d]pyrimidine

To a solution of3-(2-tert-butyl-4-chloro-5-methyl-phenoxymethyl)-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine(750 mg) in anhydrous THF (100 mL) was added m-CPBA (1.03 g) at 25° C.and the reaction mixture was stirred at 25° C. for 16 h. The mixture wasdiluted with EtOAc and washed with saturated aqueous sodium thiosulphatesolution and brine. The organic layer was dried over Na₂SO₄, filteredand evaporated under reduced pressure. The resulting residue waspurified by column chromatography over silica gel (30-50% EtOAc inhexane) to afford the title compound (580 mg, 71%) as an off whitesolid. MS (ESI): m/z=409.3 [M+H]⁺.

Step 4:2-{[3-(2-tert-Butyl-4-chloro-5-methyl-phenoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-methyl-amino}-ethanol

To a solution of3-(2-tert-butyl-4-chloro-5-methyl-phenoxymethyl)-6-methanesulfonyl-1H-pyrazolo[3,4-d]pyrimidine(45 mg) in dioxane (10 mL) at 25° C. were added 2-methylaminoethanol(24.82 mg) followed by Et₃N (0.03 mL) and the reaction mixture washeated to reflux for 3 h. The mixture was cooled to 25° C. and allvolatiles were removed under reduced pressure. The residue was purifiedby column chromatography over silica gel (60-70% EtOAc in hexane) toafford the title compound (12 mg, 27%) as an off white solid. MS (ESI):m/z=404.4 [M+H]⁺.

The following examples were synthesized in analogy to example D26 from3-(2-tert-butyl-4-chloro-5-methyl-phenoxymethyl)-6-methanesulfonyl-1H-pyrazolo[3,4-d]pyrimidine(example D26, step 3) under similar reaction conditions as described inexample D26, step 4, with a suitable amine reagent:

Ex. Systematic Name Amine reagent MS, m/z D27

3-methylamino-propane-1,2- diol 434.2 [M + H]⁺ D29

3-(hydroxy)azetidine hydrochloride 402.3 [M + H]⁺ D30

2-amino-ethanol 390.4 [M + H]⁺

Example D312-[[3-[(2-tert-Butyl-4-chloro-&-methylphenoxy)methyl]-1H-pyrazolo[3,4-d]pyrimidin-6-yl]oxy]ethanol

A mixture of3-(2-tert-butyl-4-chloro-5-methyl-phenoxymethyl)-6-methanesulfonyl-1H-pyrazolo[3,4-d]pyrimidine(150 mg, example D26, step 3), ethane-1,2-diol (1 mL) and Et₃N (0.103mL) was heated to 100° C. for 6 h. The reaction mixture was cooled to25° C., diluted with EtOAc and washed with water and brine. The organiclayer was dried over Na₂SO₄, filtered and evaporated under reducedpressure. The residue was purified by prep. HPLC to afford the titlecompound (29 mg, 20%) as off white solid. MS (ESI): m/z=391.2 [M+H]⁺.

Example D325-tert-Butyl-4-[[6-(3-hydroxyazetidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]methoxy]-2-methylbenzonitrile

Step 1:5-tert-Butyl-4-[1-(4-methoxy-benzyl)-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidin-3-ylmethoxy]-2-methyl-benzonitrile

The title compound was prepared in analogy to example D26, step 1 from3-bromomethyl-1-(4-methoxy-benzyl)-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine(400 mg. Intermediate D26-B) and5-tert-butyl-4-hydroxy-2-methyl-benzonitrile (259.31 mg, IntermediateA16) and was obtained as off white solid (450 mg, 87%). MS (ESI):m/z=488.5 [M+H]⁺.

Step 2:5-tert-Butyl-2-methyl-4-(6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidin-3-ylmethoxy)-benzonitrile

The title compound was prepared in analogy to example D26, step 2 from5-tert-butyl-4-[1-(4-methoxy-benzyl)-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidin-3-ylmethoxy]-2-methyl-benzonitrile(450 mg) and was obtained as an off white solid (225 mg, 66%). MS (ESI):m/z=368.2 [M+H]⁺.

Step 3:5-tert-Butyl-4-(6-methanesulfonyl-1-pyrazolo[3,4-d]pyrimidin-3-ylmethoxy)-2-methyl-benzonitrile

The title compound was prepared in analogy to example D26, step 3, from5-tert-butyl-2-methyl-4-(6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidin-3-ylmethoxy)-benzonitrile(700 mg) and was obtained as an off white solid (580 mg, 76%). MS (ESI):m/z=400.2 [M+H]⁺.

Step 4:5-tert-Butyl-4-[[6-(3-hydroxyazetidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]methoxy]-2-methylbenzonitrile

The title compound was prepared in analogy to example D26, step 4, from5-tert-butyl-4-(6-methanesulfonyl-1H-pyrazolo[3,4-d]pyrimidin-3-ylmethoxy)-2-methyl-benzonitrile(100 mg) and 3-(hydroxy)azetidine hydrochloride (82.0 mg) and wasobtained as an off white solid (35 mg, 36%). MS (ESI): m/z=393.3 [M+H]⁺.

The following examples were synthesized in analogy to example D32 from5-tert-butyl-4-(6-methanesulfonyl-1H-pyrazolo[3,4-d]pyrimidin-3-ylmethoxy)-2-methyl-benzonitrile(example D32, step 3) under similar reaction conditions as described inexample D26, step 4, with a suitable amine reagent:

Ex. Systematic Name Amine reagent MS, m/z D33

2-methylamino-ethanol 425.2 [M + H]⁺ D35

2-amino-ethanol 381.2 [M + H]⁺ D36

3-methylamino-propane-1,2-diol 395.4 [M + H]⁺

Example D343-[[3-[(2-tert-Butyl-4-chloro-5-methylphenoxy)methyl]-1H-pyrazolo[3,4-d]pyrimidin-6-yl]oxy]propane-1,2-diol

Step 1:3-(2-tert-Butyl-4-chloro-5-methyl-phenoxymethyl)-6-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-1H-pyrazolo[3,4-d]pyrimidine

A mixture of3-(2-tert-butyl-4-chloro-5-methyl-phenoxymethyl)-6-methanesulfonyl-1H-pyrazolo[3,4-d]pyrimidine(150 mg, example D26, step 3),(2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (1 mL) and Et₃N (0.103 mL)was heated to 100° C. for 3 h. The reaction mixture was cooled to 25° C.and all volatiles were evaporated under reduced pressure. The residuewas diluted with EtOAc and the organic phase was washed water and brine.The organic layer was dried over Na₂SO₄ and evaporated under reducedpressure to afford the title compound that was used in the next reactionstep without further purification. MS (ESI): m/z=461.1 [M+H]⁺.

Step 2:3-[3-(2-tert-Butyl-4-chloro-5-methyl-phenoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yloxy]-propane-1,2-diol

A solution of3-(2-tert-butyl-4-chloro-5-methyl-phenoxymethyl)-6-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-1H-pyrazolo[3,4-d]pyrimidine(135 mg) in 2N aqueous HCl (15 mL) was stirred at 25° C. for 16 h. Thereaction mixture was diluted with DCM and the organic layer wasseparated, washed with saturated aqueous NaHCO₃ solution and brine,dried over Na₂SO₄ and evaporated under reduced pressure. The residue waspurified by HPLC to afford the title compound (36 mg, 29%) as an offwhite solid. MS (ESI): m/z=421.2 [M+H]⁺.

Example D375-tert-Butyl-4-[[6-(2,3-dihydroxypropoxy)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]methoxy]-2-methylbenzonitrile

The title compound was prepared in analogy to example D34, steps 1 and2, from5-tert-butyl-4-(6-methanesulfonyl-1H-pyrazolo[3,4-d]pyrimidin-3-ylmethoxy)-2-methyl-benzonitrile(150 mg, example D32, step 3) and was obtained as an off white solid (26mg, 18%). MS (ESI): m/z=412.2 [M+H]⁺.

Example D385-tert-Butyl-4-[[6-(2-hydroxyethoxy)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]methoxy]-2-methylbenzonitrile

The title compound was prepared in analogy to example D31 from5-tert-butyl-4-(6-methanesulfonyl-1H-pyrazolo[3,4-d]pyrimidin-3-ylmethoxy)-2-methyl-benzonitrile(105 mg, example D32, step 3) and was obtained as an off white solid (16mg, 16%). MS (ESI): m/z=382.2 [M+H]⁺.

Example D444-[3-[5-Chloro-4-methyl-2-(1H-pyrazolo[3,4-c]pyridin-3-ylmethoxy)phenyl]-4-fluorobenzoyl]-1-methylpiperazin-2-one

Step 1:4-[3-[5-Chloro-4-methyl-2-[(1-tritylpyrazolo[3,4-c]pyridin-3-yl)methoxy]phenyl]-4-fluorobenzoyl]-1-methylpiperazin-2-one

In a 20 mL round-bottomed flask,4-(5′-chloro-6-fluoro-2′-hydroxy-4′-methyl-[1,1′-biphenyl]-3-carbonyl)-1-methylpiperazin-2-one(Intermediate B65, 50 mg),3-(chloromethyl)-1-trityl-1H-pyrazolo[3,4-c]pyridine (IntermediateD44-B, 54.4 mg) and potassium carbonate (40.3 mg) were combined withacetone (6 mL) to give a white suspension. The mixture was then heatedto 50° C. and was stirred for 4 h, but no reaction could be observed.Therefore, acetone was removed in vacuo and acetonitrile (6 mL) andcesium carbonate (95 mg) were added. The mixture was then heated againat 80° C. for 4 hours. The solvent was removed in vacuo and to the lightbrown residue was added saturated aqueous NH₄Cl solution. The mixturewas extracted 3 times with ethyl acetate and the combined organic layerswere dried over Na₂SO₄ and concentrated in vacuo to give a light brownfoam. The crude material was purified by flash chromatography (silicagel, 20 g, gradient of 0% to 100% ethyl acetate in heptane, followed by0% to 10% MeOH in DCM) to afford the title compound as a colorless foam(53 mg). MS (m/z): 750.26 [M+H]⁺.

Step 2:4-[3-[5-Chloro-4-methyl-2-(1H-pyrazolo[3,4-c]pyridin-3-ylmethoxy)phenyl]-4-fluorobenzoyl]-1-methylpiperazin-2-one

In a 10 mL round-bottomed flask,4-(5′-chloro-6-fluoro-4′-methyl-2′-((1-trityl-1H-pyrazolo[3,4-c]pyridin-3-yl)methoxy)-[1,1′-biphenyl]-3-carbonyl)-1-methylpiperazin-2-one(50 mg) was dissolved in CH₂Cl₂ (2.9 mL) to give a colorless solution.TFA (444 μL) was added at rt and the reaction mixture was stirred for 30min TLC analysis confirmed the consumption of the starting material andformation of a single product. The reaction was then quenched by carefuladdition of sat. Na₂CO₃ solution. The mixture was extracted with DCM(2×25 mL) and the combined organic extracts were washed with brine,dried over Na₂SO₄, and evaporated to provide the title compound as acolorless foam (27.0 mg). MS (m/z): 508.15 [M+H]⁺.

The following examples were synthesized from the suitable buildingblocks/intermediates in analogy to example D44, Steps 1-2:

Building block/ Ex. Systematic Name intermediates MS, m/z D46

Intermediate D44-B and Intermediate B64 483.3 [M + H]⁺ D47

Intermediate D44-B and Intermediate B53 381.2 [M + H]⁺ D49

Intermediate D44-B and Intermediate A17 321.2 [M + H]⁺

The following additional examples of type D were synthesized from thesuitable building blocks/intermediates in analogy to Example D44, Steps1-2:

Building block/ Ex. Systematic Name intermediates MS, m/z D50

Intermediate D44-B and Intermediate A34 341.2 [M + H]⁺ D51

Intermediate D44-B and Intermediate B95 435.2 [M + H]⁺ D54

Intermediate D54-B and Intermediate B97 463.1 [M + H]⁺

The following additional examples of type D were synthesized from thesuitable building blocks/intermediates in analogy to Example D17:

D52

tert-butyl 3-(bromomethyl)- pyrazolo[3,4-b]pyridine-1- carboxylate (CAS:174180-76-8) and Intermediate A34 341.2 [M + H]⁺ D53

tert-butyl 3-(bromomethyl)- pyrazolo[3,4-b]pyridine-1- carboxylate (CAS:174180-76-8) and Intermediate B95 435.1 [M + H]⁺ D55

tert-butyl 3-(bromomethyl)- pyrazolo[3,4-b]pyridine-1- carboxylate (CAS:174180-76-8) and Intermediate B97 463.1 [M + H]⁺

Examples E: Examples Related to Tetrahdro-Pyrazolopyridine Head GroupsExample E1 tert-Butyl3-((2-tert-butyl-4-chloro-5-methylphenoxy)methyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate

Step 1: 5-tert-Butyl 3-ethyl6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-3,5(4H)-dicarboxylate

Di-tert-butyl-dicarbonate (1.04 g) was added to a suspension of ethyl4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (930 mg,CAS: 926926-62-7) in diethyl ether (45 mL) at 0° C. Following additionof the reagents, the reaction mixture was stirred at rt overnight. Waterwas added and the mixture was extracted with EtOAc. The combined organiclayers were washed with water and brine, dried over Na₂SO₄ andevaporated. The residue was purified by column chromatography (50 gsilica gel; heptane/EtOAc 70/30-45/55) to obtain the title compound as awhite foam (1.079 g, 77%). MS (ESI): m/z=294.2 [M−H]⁻.

Step 2: tert-Butyl3-(hydroxymethyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate

A solution of 5-tert-butyl 3-ethyl6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-3,5(4H)-dicarboxylate (60.0 mg)in THF (0.5 mL) was added dropwise at 0° C. to a white suspension ofcalcium chloride (90.1 mg) and sodium borohydride (61.4 mg) in a mixtureof EtOH (1 mL) and THF (0.5 mL). The resulting white suspension wasstirred at 0° C. overnight. Then, 0.1N HCl was added carefully and themixture was extracted with EtOAc. The combined organic layers werewashed with brine, dried over Na₂SO₄ and evaporated. The residue waspurified by column chromatography (5 g silica gel; DCM/MeOH 98/2-95/5)to afford the title compound as a white solid (47 mg, 92%). MS (ESI):m/z=254.2 [M+H]⁺.

Step 3: tert-Butyl3-(chloromethyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate

tert-Butyl3-(hydroxymethyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate(94.0 mg) was suspended in a mixture of DCM (1 mL), acetonitrile (1 mL)and THF (1 mL). Triphenylphosphine (102 mg) and carbon tetrachloride(285 mg, 179 μL) were added to the white suspension and the mixture wasstirred at rt. After awhile the reaction mixture turned into a colorlesssolution, which was stirred at rt for 2 d. Additional carbontetrachloride (285 mg, 179 μL) was added and the solution was stirredfor 1 more day at rt. Then, the mixture was concentrated to dryness andthe residue was purified by column chromatography (20 g silica gel;DCM/MeOH 98/2-90/10) to obtain the title compound as white solid (37 mg,35%). MS (ESI): m/z=272.2 [M+H]⁺.

Step 4: tert-Butyl3-((2-tert-butyl-4-chloro-5-methylphenoxy)methyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate

A mixture of tert-butyl3-(chloromethyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate(45.1 mg), 2-tert-butyl-4-chloro-5-methyl-phenol (82.5 mg, CAS:30894-16-7) and potassium carbonate (57.4 mg) in acetonitrile (2 mL) washeated to reflux for 5 h. The reaction mixture was cooled to rt and wasthen concentrated. The residue was partitioned between EtOAc and water.The aqueous layer was extracted with EtOAc and the combined organiclayers were washed with brine, dried over Na₂SO₄ and evaporated. Theremaining oil was purified by column chromatography (10 g silica gel;heptane/EtOAc 70/30-10/90) to afford the title compound as a white solid(19 mg, 26%). MS (ESI): m/z=434.3 [M+H]⁺.

Example E21-(3-((2-tert-Butyl-4-chloro-5-methylphenoxy)methyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

Step 1: 5-tert-Butyl 3-ethyl1-trityl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate and5-tert-Butyl 3-ethyl2-trityl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate

A solution of 5-tert-butyl 3-ethyl6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-3,5(4H)-dicarboxylate (1.17 g.example E1, step 1) in DMF (7 mL) was added dropwise to a suspension ofsodium hydride (216 mg, 55% in mineral oil) in DMF (7 mL) at 0° C. Thereaction mixture was stirred at 0° C. for 15 min and then at rt for 30min. The mixture was then again cooled to 0° C. and a solution of[chloro(diphenyl)methyl]benzene (1.16 g) in DMF (7 mL) was added. Theresulting suspension was stirred at rt for 2 d. Water was addedcarefully and the mixture was extracted with EtOAc. The combinedextracts were washed with water (3 times) and brine, dried over Na₂SO₄and evaporated. The residue was purified by column chromatography (120 gsilica gel; heptane/EtOAc 95/5-25/75) to obtain 5-tert-butyl 3-ethyl1-trityl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate (offwhite solid, 790 mg, 37%. MS (ESI): m/z=560.4 [M+Na]⁺) as well as5-tert-butyl 3-ethyl2-trityl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate (whitesolid, 450 mg, 21%). MS (ESI): m/z=560.4 [M+Na]⁺).

Step 2: tert-Butyl3-(hydroxymethyl)-1-trityl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate

To a solution of 5-tert-butyl 3-ethyl1-trityl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate (200mg) in THF (3 mL) was added dropwise diisobutylaluminum hydride (818 μL,1M in toluene) at 0° C. After the addition, the colorless solution wasstirred at rt overnight. 0.5 mL MeOH were added with vigorous stirringand the resulting solution was poured into a mixture of 20 mL 10 wt %Rochelle-salt solution and 20 mL EtOAc. This mixture was stirred at rtfor 1 h and the layers were then separated. The aqueous layer wasextracted with EtOAc and the combined organic layers were washed withbrine, dried over Na₂SO₄ and evaporated. The residue was purified bycolumn chromatography (20 g silica gel; heptane/EtOAc 80/20-50/50) toobtain the title compound as a white solid (156 mg, 85%). MS (ESI):m/z=518.4 [M+Na]⁺).

Step 3: tert-Butyl3-[(2-tert-butyl-4-chloro-5-methyl-phenoxy)methyl]-1-trityl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate

To a solution of tert-butyl3-(hydroxymethyl)-1-trityl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(100 mg) in 2-methyltetrahydrofuran (1 mL) was added triethylamine (22.5mg, 30.9 μL) at 0° C. To this mixture was added dropwise methanesulfonylchloride (24.3 mg, 16.5 μL) and the resulting mixture was stirred at 0°C. for 1 h. A white solid precipitated which was filtered off and washedwith 2-methyltetrahydrofuran. The filtrate was concentrated and theremaining colorless oil was dissolved in DMA (0.5 mL) and the resultingsolution was added dropwise to a suspension of2-tert-butyl-4-chloro-5-methyl-phenol (40.1 mg, CAS: 30894-16-7),potassium iodide (56.9 mg) and cesium fluoride (153 mg) in DMA (1 mL).The reaction mixture was stirred at rt overnight. Water was added andthe mixture was extracted with EtOAc. The combined organic layers werewashed with water (3 times) and brine, dried over Na₂SO₄ and evaporated.The residue was purified by column chromatography (20 g silica gel;heptane/EtOAc 98/2-50/50) to obtain the title compound as an off whitesolid (49 mg, 36%). MS (ESI): m/z=674.5 [M−H]⁻.

Step 4:3-[(2-tert-Butyl-4-chloro-5-methyl-phenoxy)methyl]-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

Trifluoroacetic acid (0.2 mL) was added to a solution of tert-butyl3-[(2-tert-butyl-4-chloro-5-methyl-phenoxy)methyl]-1-trityl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(47.0 mg) in DCM (1 mL) at rt. After 30 min, saturated Na₂CO₃ solutionwas added carefully and the mixture was extracted with DCM. The combinedextracts were washed with a small amount of brine, dried over Na₂SO₄ andevaporated. The residue was purified by column chromatography (5 gsilica gel; DCM/MeOH 95/5-85/15) to obtain the title compound as a whitesolid (18 mg, 78%). MS (ESI): m/z=334.2 [M+H]⁺.

Step 5:1-(3-((2-tert-Butyl-4-chloro-5-methylphenoxy)methyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

A mixture of3-[(2-tert-butyl-4-chloro-5-methyl-phenoxy)methyl]-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(15.0 mg), triethylamine (9.09 mg, 12.5 μL) and acetyl chloride (3.52mg, 3.19 μL) in THF (0.5 mL) was stirred at rt overnight. Then, waterwas added and the mixture was extracted with EtOAc and then with DCM.The combined extracts were washed with brine, dried over Na₂SO₄ andevaporated. The residue was purified by column chromatography (5 gsilica gel; DCM/MeOH 19/1) to obtain the title compound as a white solid(13 mg, 77%). MS (ESI): m/z=376.2 [M+H]⁺.

Example E31-(3-((2-tert-Butyl-4-chloro-5-methylphenoxy)methyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)-2-methoxyethanone

The title compound was prepared in analogy to example E2, step 5, from3-[(2-tert-butyl-4-chloro-5-methyl-phenoxy)methyl]-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(15.0 mg) and 2-methoxyacetyl chloride (5.11 mg, 4.27 μL) and wasobtained as a white solid (13 mg, 71%). MS (ESI): m/z=406.3 [M+H]⁺.

Example E43-((2-tert-Butyl-4-chloro-5-methylphenoxy)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine

Step 1: tert-Butyl4-(1-diazo-2-ethoxy-2-oxo-ethyl)-4-hydroxy-piperidine-1-carboxylate

A lithium diisopropylamide solution was prepared by dropwise addition ofnBuLi (19.1 mL, 1.6 M in hexane) to a solution of diisopropylamine (3.12g, 4.4 mL) in dry THF (77 mL) at −78° C. This lithium diisopropylamidesolution was then added dropwise over 1 hour to a solution of tert-butyl4-oxopiperidine-1-carboxylate (3.854 g) and ethyl diazoacetate (2.31 g,2.1 mL) in dry THF (115 mL) at −78° C. The mixture was stirred for 2hours at −78° C. Then, AcOH (5.81 g, 5.54 mL) was added at −78° C. andthe mixture was then kept at rt overnight. The solvent was removed underreduced pressure to approx. 1/10 of its volume and diethyl ether (400mL) was added. The mixture was washed with saturated NaHCO₃ solution andwas then dried over Na₂SO₄, filtered and evaporated. The remainingorange-brown viscous oil (6.46 g) was used without further analysis inthe next reaction step.

Step 2: tert-Butyl4-(1-diazo-2-ethoxy-2-oxo-ethyl)-3,6-dihydro-2H-pyridine-1-carboxylate

Pyridine (30.5 g, 31.2 mL) was added to a solution of tert-butyl4-(1-diazo-2-ethoxy-2-oxo-ethyl)-4-hydroxy-cyclohexanecarboxyate (6.05g) in MTBE (120 mL). The mixture was cooled to −10° C. and phosphorusoxychloride (5.92 g, 3.6 mL) was added dropwise over 8 minutes undervigorous stirring. The mixture was slowly warmed to rt and was stirredovernight. The mixture was cooled again to −10° C. and more phosphorusoxychloride (592 mg, 360 μL) was added dropwise. The reaction mixturewas slowly warmed to rt and stirred for 3 h before 0.1M NaOH (193 mL)was added slowly. The mixture was extracted with EtOAc and the combinedextracts were washed with brine, dried over Na₂SO₄, filtered andevaporated. The residue (6.2 g) was used in the next reaction stepwithout further purification. MS (ESI): m/z=294.2 [M−H]⁻.

Step 3: 6-tert-Butyl 3-ethyl1,4,5,7-tetrahydropyrazolo[3,4-c]pyridine-3,6-dicarboxylate

In a two-neck flask equipped with a dropping funnel and a distillationcolumn, toluene (80 mL) was heated to reflux. A solution of tert-butyl4-(1-diazo-2-ethoxy-2-oxo-ethyl)-3,6-dihydro-2H-pyridine-1-carboxylate(5.7 g) in a mixture of EtOAc (20 mL) and pyridine (8 mL) was added viathe dropping funnel at the same rate as the rate of distillation. Moretoluene (7 mL) was added. The dark brown mixture was stirred for an hourand was then allowed to cool to rt. EtOAc (250 mL) was added and themixture was washed with water (3 times) and brine, dried over Na₂SO₄,filtered and evaporated. The crude material was purified by columnchromatography (50 g silica gel; heptane/EtOAc 9/1 to 1/1) to obtain thetitle compound as light brown solid (3.12 g, 55%). MS (ESI): m/z=294.2[M−H]⁻.

Step 4: 6-tert-Butyl 3-ethyl1-trityl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-3,6-dicarboxylate and6-tert-Butyl 3-ethyl2-trityl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-3,6-dicarboxylate

In analogy to example E2, step 1, 6-tert-butyl 3-ethyl1,4,5,7-tetrahydropyrazolo[3,4-c]pyridine-3,6-dicarboxylate (980 mg) wasconverted into 6-tert-butyl 3-ethyl1-trityl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-3,6-dicarboxylate (whitesolid, 762 mg, 43%, MS (ESI): m/z=1097.8 [2M+Na]⁺) and 6-tert-butyl3-ethyl2-trityl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-3,6-dicarboxylate (whitesolid, 510 mg, 290%). MS (ESI): m/z=560.4 [M+Na]⁺).

Step 5: tert-Butyl3-(hydroxymethyl)-1-trityl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate

From 6-tert-butyl 3-ethyl1-trityl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-3,6-dicarboxylate (715mg) the title compound was obtained in analogy to example E2, step 2, asa white solid (581 mg, 88%). MS (ESI): m/z=496.3 [M+H]⁺.

Step 6: tert-Butyl3-[(2-tert-butyl-4-chloro-5-methyl-phenoxy)methyl]-1-trityl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate

From tert-butyl3-(hydroxymethyl)-1-trityl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate(100 mg) the title compound was obtained in analogy to example E2, step3, as a light yellow foam (58 mg, 43%). MS (ESI): m/z=698.5 [M+Na]⁺.

Step 7:3-((2-tert-Butyl-4-chloro-5-methylphenoxy)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine

From tert-butyl3-[(2-tert-butyl-4-chloro-5-methyl-phenoxy)methyl]-1-trityl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate(75.7 mg) the title compound was obtained in analogy to example E2, step4, as a light yellow solid (29 mg, 78%). MS (ESI): m/z=334.2 [M+H]⁺.

Example E51-(3-((2-tert-Butyl-4-chloro-5-methylphenoxy)methyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)ethanone

The title compound was prepared in analogy to example E2, step 5, from3-((2-tert-butyl-4-chloro-5-methylphenoxy)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine(25.0 mg example 4) and acetyl chloride (5.88 mg, 5.33 μL) and wasobtained as a white solid (19 mg, 67%). MS (ESI): m/z=376.2 [M+H]⁺.

Example E61-(3-((2-tert-Butyl-4-chloro-5-methylphenoxy)methyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)-2-methoxyethanone

The title compound was prepared in analogy to example E2, step 5, from3-((2-tert-butyl-4-chloro-5-methylphenoxy)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine(22.0 mg, example 4) and 2-methoxyacetyl chloride (7.51 mg, 6.27 μL) andwas obtained as a white solid (17 mg, 64%). MS (ESI): m/z=406.2 [M+H]⁺.

Example E73-((4-Chloro-2-(2-methoxypyridin-3-yl)-5-methylphenoxy)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine

Triethylamine (26.9 mg, 37.1 μL) was added to a solution of tert-butyl3-(hydroxymethyl)-1-trityl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate(120 mg, obtained in example E4, step 5) in 2-methyltetrahydrofuran (1.5mL) at 0° C. To the mixture was added dropwise methanesulfonyl chloride(29.1 mg, 19.7 μL) and the resulting mixture was stirred at 0° C. for 1h. The suspension was then filtered, the filtercake was washed with2-methyltetrahydrofuran and the filtrate was concentrated. The residuewas dissolved in DMA (1.5 mL) and this solution was added dropwise to asuspension of 4-chloro-2-(2-methoxy-3-pyridyl)-5-methyl-phenol (60.4 mg.Intermediate B53), potassium iodide (68.2 mg) and cesium fluoride (184mg) in DMA (1.5 mL) and the reaction mixture was stirred at rtovernight. Then, water was added and the mixture was extracted withEtOAc. The combined organic layers were washed with water (3 times) andbrine, dried over Na₂SO₄ and evaporated. The residue was purified bycolumn chromatography (20 g silica gel; heptane/EtOAc 90/10-50/50) toobtain a yellow foam (81 mg) that was dissolved in a mixture of DCM (2mL) and trifluoroacetic acid (0.2 mL). This mixture was stirred at rtfor 1 h. Then, saturated Na₂CO₃ solution was added carefully and themixture was extracted with DCM. The combined organic layers were washedwith a very small amount of brine, dried over Na₂SO₄ and evaporated. Theremaining residue was purified by column chromatography (5 g silica gel;DCM/MeOH 95/5+DCM/MeOH/NH₄OH 8/1.9/0.1) to obtain the title compound asa white foam (21 mg, 23%). MS (ESI): m/z=385.2 [M+H]⁺.

Example E81-(3-((4-Chloro-2-(2-methoxypyridin-3-yl)-5-methylphenoxy)methyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)ethanone

The title compound was prepared in analogy to example E2, step 5, from3-((4-chloro-2-(2-methoxypyridin-3-yl)-5-methylphenoxy)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine(25.0 mg, example E7) and acetyl chloride (5.88 mg, 5.33 μL) and wasobtained as a white solid (8 mg, 42%). MS (ESI): m/z=427.2 [M+H]⁺.

Examples F: Examples Related to Pyrazole Head Groups Example F13-((2-tert-Butyl-4-chloro-5-methylphenoxy)methyl)-1H-pyrazole

Step 1: tert-Butyl3-[(2-tert-butyl-4-chloro-5-methyl-phenoxy)methyl]pyrazole-1-carboxylate

A mixture of tert-butyl 3-(bromomethyl)pyrazole-1-carboxylate (65.8 mg,Intermediate F1), 2-tert-butyl-4-chloro-5-methyl-phenol (50 mg. CAS:30894-16-7) and potassium carbonate (87.1 mg) in acetone (5 mL) washeated to 50° C. After 6 h and after 7.5 h, more2-tert-butyl-4-chloro-5-methylphenol (10 mg and 22 mg, respectively) wasadded and heating was continued for 4 h. Sat. NH₄Cl solution was addedand the mixture was extracted with EtOAc. The combined extracts werewashed with brine, dried with Na₂SO₄ and evaporated. The residue waspurified by column chromatography (20 g SiO₂, n-heptane/EtOAc 100/0 to65/35) to obtain the title compound (71 mg, 74%) as colorless oil. MS(ESI): m/z=279.2 [M-CO₂tBu+H]⁺.

Step 2: 3-((2-tert-Butyl-4-chloro-5-methylphenoxy)methyl)-1H-pyrazole

A solution of tert-butyl3-[(2-tert-butyl-4-chloro-5-methyl-phenoxy)methyl]pyrazole-1-carboxylate(65 mg) in a mixture of DCM (1 mL) and TFA (1 mL) was stirred at rt for4 h. Then, saturated NaHCO₃ solution was added and the mixture wasextracted with EtOAc. The combined extracts were washed with brine,dried with Na₂SO₄ and evaporated to provide the title compound (47 mg,98%) as a colorless viscous oil. MS (ESI): m/z=279.2 [M+H]⁺.

Example F24-((1H-Pyrazol-3-yl)methoxy)-5-tert-butyl-2-methylbenzonitrile

The title compound was prepared in analogy to example F1, steps 1 and 2,from tert-butyl 3-(bromomethyl)pyrazole-1-carboxylate (Intermediate F1)and 5-tert-butyl-4-hydroxy-2-methyl-benzonitrile (Intermediate A16) andwas obtained as white foam. MS (ESI): m/z=270.2 [M+H]⁺.

Example F3 Methyl3-((2-(tert-butyl)-4-chloro-5-methylphenoxy)methyl)-1H-pyrazole-5-carboxylate

Step 1: Methyl5-[(2-tert-butyl-4-chloro-5-methyl-phenoxy)methyl]-2-tetrahydropyran-2-yl-pyrazole-3-carboxylate

Triethylamine (29 mg, 40 μL) was added to a solution of methyl5-(hydroxymethyl)-2-tetrahydropyran-2-yl-pyrazole-3-carboxylate (63 mg,Intermediate F3) in 2-methyltetrahydrofuran (1.5 mL) at 0° C. Then,methanesulfonyl chloride (30.9 mg, 21 μL) was added dropwise and thereaction mixture was stirred at 0° C. for 2 h. The white precipitate wasfiltered off and was washed with 2-methyltetrahydrofuran. The filtratewas concentrated and the residue was suspended in DMA (2.4 mL) and addedto a suspension of 2-tert-butyl-4-chloro-5-methyl-phenol (52 mg, CAS:30894-16-7), potassium iodide (76 mg) and cesium fluoride (197 mg) inDMA (1.5 mL). The reaction mixture was stirred overnight at rt. Then,water was added and the mixture was extracted with EtOAc. The combinedextracts were washed with water and brine, dried with Na₂SO₄, filteredand evaporated. The residue was purified by chromatography (20 g silicagel; heptane/EtOAc 100/0 to 1/2) to provide the title compound (22 mg,20%) as a waxy solid. MS (ESI): m/z=337.2 [M-THP+H]⁺.

Step 2: Methyl3-((2-(tert-butyl)-4-chloro-5-methylphenoxy)methyl)-1H-pyrazole-5-carboxylate

Methyl5-[(2-tert-butyl-4-chloro-5-methyl-phenoxy)methyl]-2-tetrahydropyran-2-yl-pyrazole-3-carboxylate(22 mg) was suspended in MeOH (1 mL) and HCl (4 M in 1,4-dioxane, 70 μL)was added. The colorless solution was stirred at rt for 2 h beforesaturated NaHCO₃ solution (5 mL) was added. The mixture was evaporatedto half of its volume and was then extracted with EtOAc. The combinedorganic layers washed with brine (10 mL), dried over Na₂SO₄, filteredand evaporated. The residue was purified by chromatography (10 g silicagel; heptane/EtOAc 100/0 to 70/30) to afford the title compound (16 mg,91%) as a white powder. MS (EST): m/z=337.2 [M+H]⁺.

Example F4(3-((2-(tert-Butyl)-4-chloro-5-methylphenoxy)methyl)-1H-pyrazol-5-yl)(pyrrolidin-1-yl)methanone

Step 1:[5-[(2-tert-Butyl-4-chloro-5-methyl-phenoxy)methyl]-2-tetrahydropyran-2-yl-pyrazol-3-yl]-pyrrolidin-1-yl-methanone

To a solution of pyrrolidine (12.9 mg, 15 μL) in DCM (0.3 mL) was addeda 2M solution of trimethylaluminum in hexane (90 μL) dropwise at rt andthe mixture was stirred for 15 minutes. Then, a solution of methyl5-[(2-tert-butyl-4-chloro-5-methyl-phenoxy)methyl]-2-tetrahydropyran-2-yl-pyrazole-3-carboxylate(50 mg, example F3, step 1) in DCM (0.6 mL) was added slowly. Thereaction mixture was heated to reflux overnight. The mixture wascarefully diluted with 1 M HCl, extracted with DCM, and the combinedorganic layers were dried over Na₂SO₄, filtered and evaporated. Theresidue was purified by chromatography (20 g silica gel; heptane/EtOAc100/0 to 1/1) to obtain the title compound (36 mg, 66%) as a colorlessoil. MS (ESI): m/z=376.3 [M-THP+H]⁺.

Step 2:(3-((2-(tert-Butyl)-4-chloro-5-methylphenoxy)methyl)-1H-pyrazol-5-yl)(pyrrolidin-1-yl)methanone

The title compound was prepared in analogy to example F3, step 2, from[5-[(2-tert-butyl-4-chloro-5-methyl-phenoxy)methyl]-2-tetrahydropyran-2-yl-pyrazol-3-yl]-pyrrolidin-1-ylmethanone(36 mg) and was obtained as a white solid (21 mg, 71%). MS (EST):m/z=376.3 [M+H]⁺.

Example F3-((2-(tert-Butyl)-4-chloro-5-methylphenoxy)methyl)-N,N-dimethyl-1H-pyrazole-5-carboxamide

The title compound was prepared in analogy to example F4, steps 1 and 2,from methyl5-[(2-tert-butyl-4-chloro-5-methyl-phenoxy)methyl]-2-tetrahydropyran-2-yl-pyrazole-3-carboxylate(example F3, step 1) and dimethylamine hydrochloride and was obtained asa white solid. MS (ESI): m/z=350.3 [M+H]⁺.

Example F6 4-[(2-tert-Butyl-4-chloro-5-methylphenoxy)methyl]-2H-triazole

Step 1: 1-tert-Butyl-5-chloro-4-methyl-2-prop-2-ynoxybenzene

In a 25 mL round-bottomed flask, 2-(tert-butyl)-4-chloro-5-methylphenol(CAS: 30894-16-7, 200 mg), 3-bromoprop-1-yne (80% in toluene) (225 mg,163 μL) and potassium carbonate (209 mg) were combined with CH₃CN (4 mL)to give a white suspension. The reaction mixture was stirred for 15 hand was then concentrated in vacuo. The reaction mixture was poured intoethyl acetate (25 mL) and the organic layer was washed with H₂O (1×10mL). The organic layer was dried over Na₂SO₄ and concentrated in vacuoto provide the title compound (180 mg, 74%). MS (m/z): 236.1 [M]⁺.

Step 2: 4-(2-tert-Butyl-4-chloro-5-methylphenoxy)methyl-2H-triazole

In a 25 mL round-bottomed flask,1-(tert-butyl)-5-chloro-4-methyl-2-(prop-2-yn-1-yloxy)benzene (180 mg)was combined with DMF (4 mL) and water (4 mL) to give a whitesuspension. Copper(II)sulfate pentahydrate (38 mg) and L-ascorbic acidsodium salt (304 mg) were added. The system was evacuated twice andflushed with nitrogen. Trimethylsilyl azide (746 mg) was added and thereaction mixture was heated to 90° C. for 2 h with stirring. The mixturewas diluted with H₂O (50 mL) and ethyl acetate (100 mL) and the layerswere separated. The aqueous phase was extracted with more ethyl acetate(2×50 mL). The organic layers were dried over Na₂SO₄ and concentrated invacuo to give a crude oil. The crude material was purified by flashchromatography (20 g silica gel cartridge, 0% to 10% MeOH in CH₂Cl₂) toafford the title compound as a colorless foam (80 mg, 37%). MS (m/z):280.2 [M+H]⁺.

Example F73-[(2-tert-Butyl-4-chloro-5-methylphenoxy)methyl]-5-phenyl-1H-pyrazole

Step 1: 3-(Chloromethyl)-5-phenyl-1H-pyrazole

This known intermediate (CAS: 755700-32-4) was made from(5-phenyl-1H-pyrazol-3-yl)methanol which is commercially available (CAS:179057-19-3), as follows: In a 25 mL round-bottomed flask,(5-phenyl-1H-pyrazol-3-yl)methanol (50 mg) was combined with CH₂Cl₂ (3mL) and the mixture was cooled to 0° C. under an argon atmosphere. Then,thionyl chloride (68.3 mg, 41.6 μL) was added dropwise over a period of2 minutes and after 30 minutes the ice bath was removed. The reactionmixture was allowed to stir at RT for another 2 hours. The mixture waspoured into ice and NaHCO₃ solution. The aqueous layer was thenextracted twice with ethyl acetate and the organic layers where washedwith brine, dried over Na₂SO₄ and concentrated in vacuo to give a crudelight yellow solid (55 mg, 95%) that was used without furtherpurification. MS (m/z): 193.0 [M+H]⁺.

Step 2:3-(2-tert-Butyl-4-chloro-5-methylphenoxy)methyl-5-phenyl-1H-pyrazole

2-(tert-Butyl)-4-chloro-5-methylphenol (CAS: 30894-16-7, 62.4 mg),potassium carbonate (233 mg) and 3-(chloromethyl)-5-phenyl-1H-pyrazole(55 mg) were combined with acetonitrile (4 mL) at RT under an argonatmosphere. The reaction mixture was then heated to 50° C. for 16 hours,whereas TLC confirmed formation of some product. The reaction mixturewas poured into ice/water and the aqueous layer was basified with 2MNaOH solution and was extracted twice with ethyl acetate. The organiclayers were washed once with brine, dried over Na₂SO₄, filtered andevaporated. The crude material was purified by flash chromatography (25g silica gel cartridge, 0% to 40% ethyl acetate in heptane) toprovide—besides some other unidentified materials—the title compound asa colorless solid (16 mg, 16%). MS (m/z): 355.2 [M+H]⁺.

The following examples of type F were synthesized from the suitablephenol building blocks/intermediates in analogy to Example F7, step 2:

Inter- Building block/ mediate Systematic Name intermediate MS, m/z F85-tert-Butyl-2-methyl-4-[(5-phenyl-1H- pyrazol-3-yl)methoxylbenzonitrile

5-tert-Butyl-4-hydroxy-2- methylbenzonitrile Intermediate A16 346.2 [M +H]⁺

Example A

A compound of formula (I) can be used in a manner known per se as theactive ingredient for the production of tablets of the followingcomposition:

Per tablet Active ingredient 200 mg Microcrystalline cellulose 155 mgCorn starch 25 mg Talc 25 mg Hydroxypropylmethylcellulose 20 mg 425 mg

Example B

A compound of formula (I) can be used in a manner known per se as theactive ingredient for the production of capsules of the followingcomposition:

Per capsule Active ingredient 100.0 mg Corn starch 20.0 mg Lactose 95.0mg Talc 4.5 mg Magnesium stearate 0.5 mg 220.0 mg

The invention claimed is:
 1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein: (1) R_(A) isselected from the group consisting of i) C₁-C₆-alkyl, ii)cyano-C₁-C₆-alkyl, iii) C₃-C₈-cycloalkyl, iv) halo-C₁-C₆-alkoxy, v)halo-C₁-C₆-alkyl, vi) aryl substituted with R_(G), R_(G1) and R_(G2),vii) heterocycloalkyl substituted with R_(G), R_(G1) and R_(G2), andviii) heteroaryl substituted with R_(G), R_(G1) and R_(G2); and R_(B) isselected from the group consisting of i) C₁-C₆-alkyl, ii)C₃-C₈-cycloalkyl, iii) C₁-C₆-alkylsulfonyl, iv)C₃-C₈-cycloalkylsulfonyl, v) C₁-C₆-alkylsulfonylamino, vi)C₃-C₈-cycloalkylsulfonylamino, vii) aminocarbonyl, ix) halogen, x)halo-C₁-C₆-alkoxy, xi) halo-C₁-C₆-alkyl, xii) heterocycloalkyl, andxiii) heteroaryl substituted with one H, C₁-C₆-alkyl, ortrialkylsilyl-C₁-C₆-alkoxy-C₁-C₆-alkyl; or (2) R_(A) is selected fromthe group consisting of i) cyano-C₁-C₆-alkyl, ii) C₃-C₈-cycloalkyl, iii)halo-C₁-C₆-alkoxy, iv) halo-C₁-C₆-alkyl, v) aryl substituted with R_(G),R_(G1) and R_(G2), vi) heterocycloalkyl substituted with R_(G), R_(G1)and R_(G2), and vii) heteroaryl substituted with R_(G), R_(G1) andR_(G2); and R_(B) is cyano; and: R_(C) and R_(C1) are independentlyselected from the group consisting of i) H, ii) C₁-C₆-alkyl, iii)C₃-C₈-cycloalkyl, iv) halo-C₁-C₆-alkoxy, v) halo-C₁-C₆-alkyl, and vi)halogen; or R_(B) and R_(C) together with the carbon atoms to which theyare attached form a ring system selected from the group consisting of i)C₃-C₈-cycloalkyl substituted with one to two substituent independentlyselected from H, C₁-C₆-alkyl, halo-C₁-C₆-alkoxy, halo-C₁-C₆-alkyl andC₃-C₈-cycloalkyl, ii) heterocycloalkyl substituted with one to twosubstituent independently selected from H, C₁-C₆-alkyl,halo-C₁-C₆-alkoxy, halo-C₁-C₆-alkyl and C₃-C₈-cycloalkyl, iii) arylsubstituted with one to two substituent independently selected from H,halogen, C₁-C₆-alkyl, halo-C₁-C₆-alkoxy, halo-C₁-C₆-alkyl andC₃-C₈-cycloalkyl, and iv) heteroaryl substituted with one to twosubstituent independently selected from H, halogen, C₁-C₆-alkyl,halo-C₁-C₆-alkoxy, halo-C₁-C₆-alkyl, and C₃-C₈-cycloalkyl; W is ringsystem A:

R_(D1) is selected from the group consisting of i) H, ii) C₁-C₆-alkyl,iii) halo-C₁-C₆-alkoxy, iv) halo-C₁-C₆-alkyl, and v) C₃-C₈-cycloalkyl,R_(G) is selected from the group consisting of i) H, ii) C₁-C₆-alkoxy,iii) C₁-C₆-alkoxy-C₁-C₆-alkylcarbonylamino-C₁-C₆-alkyl, iv)C₁-C₆-alkoxy-C₁-C₆-alkylcarbonyl(C₁-C₆-alkyl)amino-C₁-C₆-alkyl, v)C₁-C₆-alkoxycarbonyl, vi) C₁-C₆-alkyl, vii) C₁-C₆-alkylsulfonyl, viii)C₃-C₈-cyloalkylsulfonyl, ix) carboxy, x) cyano, xi) C₃-C₈-cycloalkyl,xii) C₃-C₈-cycloalkoxy, xiii) C₃-C₈-cycloalkylcarbonylamino-C₁-C₆-alkyl,xiv) C₃-C₈-cycloalkylcarbonyl(C₁-C₆-alkyl)amino-C₁-C₆-alkyl, xv)C₁-C₆-alkylcarbonylamino-C₁-C₆-alkyl, xvi)C₁-C₆-alkylcarbonyl(C₁-C₆-alkyl)amino-C₁-C₆-alkyl, xvii)halo-C₁-C₆-alkyl, xviii) halo-C₁-C₆-alkoxy, xix) halogen, xx) hydroxy,xxi) aminocarbonyl substituted on the nitrogen atom with RN and Ro,xxii) aminocarbonyl-C₁-C₆-alkoxy substituted on the nitrogen atom withRN and Ro, xxiii) heteroaryl substituted with one H, C₁-C₆-alkyl,C₃-C₈-cycloalkyl, alkyl, halo-C₁-C₆-alkoxy, benzyl or aryl, whereinbenzyl and aryl are substituted with one to three substituentsindependently selected from H, C₁-C₆-alkyl, C₃-C₈-cycloalkyl,halo-C₁-C₆-alkyl and halo-C₁-C₆-alkoxy, xxiv)heterocycloalkyl-C₁-C₆-alkoxy substituted with one H, C₁-C₆-alkyl,C₃-C₈-cycloalkyl, halo-C₁-C₆-alkyl, halo-C₁-C₆-alkoxy, benzyl or aryl,wherein benzyl and aryl are substituted with one to three substituentsindependently selected from H, C₁-C₆-alkyl, C₃-C₈-cycloalkyl,halo-C₁-C₆-alkyl and halo-C₁-C₆-alkoxy, and xxv)heterocycloalkyl-C₁-C₆-alkyl substituted with one H, C₁-C₆-alkyl,C₃-C₈-cycloalkyl, halo-C₁-C₆-alkyl, halo-C₁-C₆-alkoxy, benzyl or aryl,wherein benzyl and aryl are substituted with one to three substituentsindependently selected from H, C₁-C₆-alkyl, C₃-C₈-cycloalkyl,halo-C₁-C₆-alkyl and halo-C₁-C₆-alkoxy; R_(G1) and R_(G2) areindependently selected from the group consisting of i) H, ii) halogen,iii) C₁-C₆-alkyl, iv) C₃-C₈-cycloalkyl, v) halo-C₁-C₆-alkoxy, and vi)halo-C₁-C₆-alkyl; R_(N) is selected from the group consisting of i) H,ii) C₁-C₆-alkoxy, iii) C₁-C₆-alkoxy-C₁-C₆-alkyl, iv)C₁-C₆-alkoxycarbonyl-C₁-C₆-alkyl, v) C₁-C₆-alkyl, vi)carboxy-C₁-C₆-alkyl, vii) C₃-C₈-cycloalkyl, viii)C₃-C₈-cycloalkyl-C₁-C₆-alkyl, ix) hydroxy-C₁-C₆-alkyl, x) phenyl, andxi) heteroaryl-C₁-C₆-alkyl; and R_(O) is selected from the groupconsisting of i) H, and ii) C₁-C₆-alkyl; or R_(N) and R_(O) togetherwith the nitrogen atom to which they are attached form aheterocycloalkyl.
 2. The compound of claim 1, wherein the compound is:3-[(2-tert-butyl-4-chloro-5-methylphenoxy)methyl]-4-methyl-1H-1,2,4-triazol-5-one;3-[(2-tert-butyl-4-chloro-5-fluorophenoxy)methyl]-4-methyl-1H-1,2,4-triazol-5-one;3-[(3,3-dimethyl-6-propan-2-yl-1,2-dihydroinden-5-yl)oxymethyl]-4-methyl-1H-1,2,4-triazol-5-one;3-[[2-tert-butyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;3-[(2-tert-butyl-4-[1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]phenoxy]methyl-4-methyl-1H-1,2,4-triazol-5-one;3-[[2-tert-butyl-4-(1-methylimidazol-2-yl)phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;3-[[2-tert-butyl-4-(1,3-oxazol-2-yl)phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;3-[(2-tert-butyl-4-morpholin-4-ylphenoxy)methyl]-4-methyl-1H-1,2,4-triazol-5-one;3-[[2-tert-butyl-4-(3-methylimidazol-4-yl)phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;3-[[2-tert-butyl-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;3-[(4-chloro-2-cyclopropyl-5-methylsulfonylphenoxy)methyl]-4-methyl-1H-1,2,4-triazol-5-one;3-[(2-tert-butyl-4-methylsulfonylphenoxy)methyl]-4-methyl-1H-1,2,4-triazol-5-one;3-[[2-tert-butyl-4-[3-(2-trimethylsilyl-ethoxymethyl)imidazol-4-yl]phenoxy]-methyl]-4-methyl-1H-1,2,4-triazol-5-one;3-[(4-chloro-2-cyclopropyl-5-methylphenoxy)methyl]-4-methyl-1H-1,2,4-triazol-5-one;3-[(4-chloro-2-cyclohexyl-5-methylphenoxy)methyl]-4-methyl-1H-1,2,4-triazol-5-one;3-[[4-chloro-5-methyl-2-(oxan-4-yl)phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;2-chloro-4-cyclopropyl-5-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile;N-[2-chloro-4-cyclopropyl-5-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]methanesulfonamide;4-tert-butyl-3-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzamide;4-methyl-3-[(5-methyl-2-propan-2-ylphenoxy)methyl]-1H-1,2,4-triazol-5-one;3-[(4-chloro-5-methyl-2-propan-2-ylphenoxy)methyl]-4-methyl-1H-1,2,4-triazol-5-one;3-[(4-chloro-2-propan-2-ylphenoxy)methyl]-4-methyl-1H-1,2,4-triazol-5-one;3-[(6-cyclopropyl-2-methyl-1,3-benzothiazol-5-yl)oxymethyl]-4-methyl-1H-1,2,4-triazol-5-one;3-[(4-chloro-2-cyclobutyl-5-methylphenoxy)methyl]-4-methyl-1H-1,2,4-triazol-5-one;3-[[2-tert-butyl-4-(1H-imidazol-2-yl)phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;3-[[2-tert-butyl-4-(1H-imidazol-5-yl)phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;3-[(4-chloro-5-methyl-2-phenylphenoxy)methyl]-4-methyl-1H-1,2,4-triazol-5-one;3-[[4-chloro-2-(2-chlorophenyl)-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;3-[[4-chloro-2-(3-chlorophenyl)-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;3-[[4-chloro-2-(4-chlorophenyl)-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]benzonitrile;3-[[4-chloro-5-methyl-2-(3-methylsulfonylphenyl)phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;3-[[4-chloro-5-methyl-2-(2-methylsulfonylphenyl)phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;3-[[4-chloro-5-methyl-2-[3-(piperidine-1-carbonyl)phenyl]phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-N-cyclohexylbenzamide;3-[[4-chloro-5-methyl-2-[3-(morpholine-4-carbonyl)phenyl]phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]benzamide;3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-N,N-dimethylbenzamide;3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-N-phenylbenzamide;3-chloro-5-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]benzamide;3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-N-cyclopropyl-4-fluorobenzamide;3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-N-(2-methoxyethyl)benzamide;3-[[4-chloro-2-(2-chloropyridin-3-yl)-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;3-[[4-chloro-2-(6-chloropyridin-2-yl)-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;5-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]pyridine-3-carboxamide;3-[[4-chloro-2-(6-methoxypyridin-2-yl)-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;3-[(4-chloro-5-methyl-2-pyrazin-2-ylphenoxy)methyl]-4-methyl-1H-1,2,4-triazol-5-one;3-[(4-chloro-5-methyl-2-pyrimidin-2-ylphenoxy)methyl]-4-methyl-1H-1,2,4-triazol-5-one;3-[[4-chloro-5-methyl-2-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;3-[[4-chloro-5-methyl-2-(1,2-oxazol-5-yl)phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;3-[[4-chloro-5-methyl-2-(1,3-oxazol-5-yl)phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;3-[[4-chloro-5-methyl-2-(3-methylimidazol-4-yl)phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;3-[[4-chloro-2-(1H-imidazol-5-yl)-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;3-[[4-chloro-5-methyl-2-(1,3-oxazol-2-yl)phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;3-[[4-chloro-5-methyl-2-(2-methylpyrazol-3-yl)phenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;2-chloro-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]-5-phenylbenzonitrile;2-chloro-5-(4-fluorophenyl)-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile;3-[4-chloro-5-cyano-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-N-methylbenzamide,2-chloro-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]-5-[3-(1H-pyrazol-3-yl)phenyl]benzonitrile;2-chloro-5-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile;3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-N-(2-hydroxyethyl)benzamide;2-chloro-5-[3-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl]-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile;3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-4-fluoro-N,N-dimethylbenzamide;3-[4-chloro-5-cyano-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-N,N-dimethylbenzamide;3-[[4-chloro-2-[2-fluoro-5-(morpholine-4-carbonyl)phenyl]-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;2-chloro-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]-5-[3-(morpholine-4-carbonyl)phenyl]benzonitrile;methyl3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]benzoate;3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]benzoicacid; methyl3-[[3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]benzoyl]amino]propanoate;3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-N-(2-hydroxyethyl)-N-methylbenzamide;ethyl2-[[3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]benzoyl]amino]acetate;3-[[3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]benzoyl]amino]propanoicacid;2-[[3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]benzoyl]amino]aceticacid; methyl3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-4-methylbenzoate;3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-4-methylbenzoicacid;3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-N,N,4-trimethylbenzamide;3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-4-(trifluoromethoxy)benzamide;3-[[4-chloro-2-(2-methoxypyridin-3-yl)-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;2-chloro-5-(2-methoxypyridin-3-yl)-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile;3-[[4-chloro-2-(5-ethoxy-2-fluorophenyl)-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;3-[[4-chloro-2-(2-methoxyphenyl)-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;3-[[4-chloro-2-(2-fluoro-5-propan-2-yloxyphenyl)-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;3-[[4-chloro-2-[2-fluoro-5-(2-methylpropoxy)phenyl]-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;3-[[4-chloro-2-[2-methoxy-5-(trifluoromethyl)phenyl]-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;3-[[4-chloro-2-(2-methoxy-5-propan-2-ylphenyl)-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;2-chloro-5-[2-fluoro-5-(morpholine-4-carbonyl)phenyl-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile;3-[[4-chloro-2-[2-fluoro-5-(pyrrolidine-1-carbonyl)phenyl]-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-N-cyclopropyl-4-fluoro-N-methylbenzamide;3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-4-fluoro-N-(2-hydroxyethyl)-N-methylbenzamide;4-[3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-4-fluorobenzoyl]-1-methylpiperazin-2-one;3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-N-cyclopentyl-4-fluoro-N-methylbenzamide;3-[[4-chloro-2-[2-fluoro-5-(oxolan-3-ylmethoxy)phenyl]-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-4-fluoro-N-methyl-N-(thiophen-2-ylmethyl)benzamide;3-[[4-chloro-2-[2-fluoro-5-(piperidine-1-carbonyl)phenyl]-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-N-(cyclopropylmethyl)-4-fluoro-N-methylbenzamide;3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-4-fluoro-N-methyl-N-(pyridin-2-ylmethyl)benzamide;3-[[4-chloro-2-[2-fluoro-5-(oxan-4-ylmethoxy)phenyl]-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-4-fluoro-N-(2-methoxyethyl)-N-methylbenzamide;3-[[4-chloro-2-[2-fluoro-5-(oxolan-2-ylmethoxy)phenyl]-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;2-[3[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-4-fluorophenoxy]-N,N-dimethylacetamide;1-[[3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-4-fluorophenyl]methyl]-4-methylpiperazine-2,5-dione;7-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-6-fluoro-3-methyl-1,3-benzoxazol-2-one;N-[[3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-4-fluorophenyl]methyl]-2-methoxy-N-methylacetamide;N-[[3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-4-fluorophenyl]methyl]cyclopropanecarboxamide;N-[[3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-4-fluorophenyl]methyl]-N-methylcyclopropanecarboxamide;3-[[4-chloro-2-[2-fluoro-5-[(2-oxopyrrolidin-1-yl)methyl]phenyl]-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;3-[[3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-4-fluorophenyl]methyl]-1,3-oxazolidin-2-one;N-[[3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-4-fluorophenyl]methyl]-2-methoxyacetamide;2-chloro-5-(2-fluorophenyl)-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile;2-chloro-5-(3-fluorophenyl)-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile;3-[5-chloro-4-methyl-2-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]phenyl]-4-(trifluoromethoxy)benzonitrile;2-chloro-5-[2-fluoro-5-(oxolan-2-ylmethoxy)phenyl]-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile;2-chloro-5-(2-fluoro-3-methoxyphenyl)-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile;2-chloro-5-(2-fluoro-5-propan-2-yloxyphenyl)-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile;3-[[4-chloro-2-(2-fluoro-3-methoxyphenyl)-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;2-chloro-5-(2,3-difluorophenyl)-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile;3-[[4-chloro-2-(5-cyclopropyloxy-2-fluorophenyl)-5-methylphenoxy]methyl]-4-methyl-1H-1,2,4-triazol-5-one;2-chloro-5-(5-chloro-2-fluorophenyl)-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile;2-chloro-5-(2,5-difluorophenyl)-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile;2-chloro-5-(5-cyclopropyloxy-2-fluorophenyl)-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile;or2-chloro-5-[2-fluoro-5-(trifluoromethyl)phenyl]-4-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methoxy]benzonitrile;or a pharmaceutically acceptable salt thereof.
 3. A pharmaceuticalcomposition comprising a compound of claim 1, or a pharmaceuticallyacceptable salt thereof, and a therapeutically inert carrier.
 4. Apharmaceutical composition comprising a compound of claim 2, or apharmaceutically acceptable salt thereof, and a therapeutically inertcarrier.
 5. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein the compound is manufactured by the processcomprising the reaction of a compound of formula (II) in the presence ofa compound of formula (III):

wherein X is halogen, mesylate or tosylate; and R_(A), R_(B), R_(C) andW are as defined in formula (I).
 6. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R_(A) is selected fromthe group consisting of: C₁-C₆-alkyl; cyano-C₁-C₆-alkyl;C₃-C₈-cycloalkyl; aryl substituted with R_(G), R_(G1), and R_(G2);heterocycloalkyl substituted with R_(G), R_(G1), and R_(G2); andheteroaryl substituted with R_(G), R_(G)1, and R_(G2).
 7. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, wherein R_(A)is selected from the group consisting of: C₁-C₆-alkyl; cyano-C₁-C₆alkyl;C₃-C₈-cycloalkyl; phenyl substituted with R_(G), R_(G1), and R_(G2);tetrahydropyranyl substituted with R_(G), R_(G1), and R_(G2); andheteroaryl substituted with R_(G), R_(G1), and R_(G2), whereinheteroaryl is selected from benzoxazolonyl, imidazolyl, isoxazolyl,oxazolyl, pyrazinyl, pyrazolyl, pyridinyl, and pyrimidinyl.
 8. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R_(A) is phenyl substituted with R_(G), R_(G1), and R_(G2). 9.The compound of claim 1, wherein the compound is of formula (Ib):

or a pharmaceutically acceptable salt thereof, wherein: R_(A) isC₁-C₆-alkyl and R_(B is halogen; or) R_(A) is phenyl substituted withR_(G), R_(G1), and R_(G2) and R_(B) is cyano or halogen; and R_(C) isselected from the group consisting of H, C₁-C₆-alkyl, and halogen;R_(D1) is C₁-C₆-alkyl, R_(G) is selected from the group consisting of H;C₁-C₆-alkoxy;C₁-C₆-alkoxy-C₁-C₆-alkylcarbonyl(C₁-C₆-alkyl)amino-C₁-C₆-alkyl; halogen;aminocarbonyl substituted on the nitrogen atom with R_(N) and R_(O);aminocarbonyl-C₁-C₆-alkoxy substituted on the nitrogen atom with R_(N)and R_(O); heteroaryl substituted with one H or C₁-C₆-alkyl wherein theheteroaryl is isoxazolyl, oxazolyl, or pyrazolyl; andheterocycloalkyl-C₁-C₆-alkoxy substituted with one H or C₁-C₆-alkyl,wherein the heterocycloalkyl-C₁-C₆-alkoxy is tetrahydropyranylmethoxy ortetrahydrofuranylmethoxy; R_(G2) is H and R_(G1) is H or halogen; R_(N)is C₁-C₆-alkoxy-C₁-C₆-alkyl and C₁-C₆-alkyl; and R_(O) is C₁-C₆-alkyl;or R_(N) and R_(O) together with the nitrogen atom to which they areattached form morpholinyl, pyrrolidinyl, or methylpiperazinonyl.
 10. Apharmaceutical composition comprising a compound of claim 9, or apharmaceutically acceptable salt thereof, and a therapeutically inertcarrier.